|
LIVIO BRASILI
COLLABORATORE DI RICERCA Dipartimento di Scienze della Vita sede ex-Scienze Farmaceutiche
|
Home |
Curriculum(pdf) |
Pubblicazioni
- Pyrimidinyl or Purinyl 1,3-Dioxolanes and 1,3-Dithiolanes, Methods for their Preparation and Their Use as Virucides
[Brevetto]
Belleau, B.; Brasili, Livio; NGUYEN BA, N.; Laval, C. C. K.
abstract
A serie of 1,3-oxathiolane and 1,3-dithiolane nucleoside have been synthetized and anti-HIV activity evaluated
- Substituted 1,3-oxathiolanes and Substituted 1,3-Dithiolanes with Antiviral Properties
[Brevetto]
Belleau, B.; NGUYEN BA, N.; Laval, C. C. K.; Mansour, T.; Jin, H.; Brasili, Livio
abstract
A serie of 1,3-oxathiolane and 1,3-dithiolane were synthetized and their anti-HIV activity evaluated.
2023
- BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting
[Articolo su rivista]
Sorbi, C.; Belluti, S.; Atene, C. G.; Marocchi, F.; Linciano, P.; Roy, N.; Paradiso, E.; Casarini, L.; Ronsisvalle, S.; Zanocco-Marani, T.; Brasili, L.; Lanfrancone, L.; Imbriano, C.; Di Rocco, G.; Franchini, S.
abstract
: The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer.
2022
- Effect of the replacement of the o-methoxyphenyl moiety with nitrogen-containing aromatic rings within N-phenyl-piperazine and phenoxy-ethylamine-based 1,3-dioxo/oxathio/dithiolanes as α1 and 5-HT1A receptor ligands
[Articolo su rivista]
Sorbi, Claudia; Franchini, Silvia; Buccioni, Michela; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio
abstract
In the present work, nineteen analogues of 1-[(2,2-Diphenyl-1,3-dioxolan-4-yl)methyl]-4-(2-methoxyphenyl)piperazine 5 and N-[2-(2-Methoxyphenoxy)ethyl]-2,2-diphenyl-1,3-dioxolane-4-methanamine 18 were synthesized. The compounds were tested for binding affinity at 5-HT1AR and α1-AR subtypes. They were also tested using functional assays as α1-AR antagonists and the most promising were tested for functional activity at 5-HT1AR, where they were shown to behave as agonists. The results highlight that the replacement of the 1,3-dioxolane ring with a 1,3-oxathiolane or a 1,3-dithiolane moiety leads to an overall reduction in in-vitro affinity at the α1-AR, while affinity, potency and efficacy were strongly enhanced at the 5-HT1A receptor. Overall, the nitrogen-containing aromatic moieties scarcely affect the affinity at the 5-HT1A receptor, while reducing potency and increasing efficacy. The oxidation of the sulphur atom in the 1,3-oxathiolane to give sulfoxides and solfones has a negative effect on affinity and potency at both receptor systems. Regardless of the effect on the other parameters, selectivity toward 5-HT1AR with respect to the α1-AR is often favoured, but never the contrary. The most striking result is the inversion of selectivity. In fact, while the lead 5 is 100-fold selective for α1-AR, the new derivatives, although to differing degrees, are selective for 5-HT1AR.
2021
- Fallot's tetralogy and squatting position
[Articolo su rivista]
Pique, M.; Brasili, L.; Putoto, G.; Iughetti, L.
abstract
The paper presents the case of a 1-year-old girl with severe respiratory distress, perioral cyanosis and severe desaturation (SpO2 35% with oxygen in nasal prongs).An echocardiogram was readily performed showing the distinctive features of Fallot’s tetralogy.The child was placed in a squatting position (knee-chest position). Subcutaneous morphine at a dose of 0.2 mg/kg, bolus of physiological solution in 30 minutes and therapy with oral propanolol were administered, with progressive clinical improvement. Subsequently, corrective cardiac surgery was performed with regular postoperative period and following good clinical conditions. Cardiogenic causes must be considered among the causes of respiratory distress especially in low resource countries where congenital heart disease can be misdiagnosed or diagnosed belatedly.
2021
- Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
[Articolo su rivista]
Linciano, P.; Benedetti, R.; Pinzi, L.; Russo, F.; Chianese, U.; Sorbi, C.; Altucci, L.; Rastelli, G.; Brasili, L.; Franchini, S.
abstract
Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
2020
- Identification of a Potent and Selective 5-HT1AReceptor Agonist with In Vitro and In Vivo Antinociceptive Activity
[Articolo su rivista]
Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrozny, M.; Pawlowska, A.; Bielenica, A.; Orzelska-Gorka, J.; Kedzierska, E.; Biala, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satala, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S.
abstract
Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.
2020
- Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents
[Articolo su rivista]
Franchini, S.; Linciano, P.; Puja, G.; Tait, A.; Borsari, C.; Denora, N.; Iacobazzi, R. M.; Brasili, L.; Sorbi, C.
abstract
Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration.
2020
- Spiroxatrine derivatives towards 5-HT1A receptor selectivity
[Articolo su rivista]
Sorbi, C.; Tait, A.; Battisti, U. M.; Brasili, L.
abstract
Background: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). Methods: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. Results: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a μM–nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. Conclusions: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2. Graphic abstract: [Figure not available: see fulltext.]
2019
- 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity
[Articolo su rivista]
Franchini, S.; Sorbi, C.; Linciano, P.; Carnevale, G.; Tait, A.; Ronsisvalle, S.; Buccioni, M.; Del Bello, F.; Cilia, A.; Pirona, L.; Denora, N.; Iacobazzi, R. M.; Brasili, L.
abstract
A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.
2019
- Effect of the rigidification of propranolol, a mixed β-adrenoceptor and 5-HT1AR antagonist
[Articolo su rivista]
Franchini, S.; Sorbi, C.; Linciano, P.; Brasili, L.; Tait, A.
abstract
Propranolol is a popular β adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT1A/B. In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at β-adrenoreceptors and 5-HT1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at β1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT1AR activity.
2019
- IDENTIFICATION OF POTENT 1,3-DIOXOLANE-BASED 5-HT1A RECEPTOR AGONISTS FOR THE TREATMENTS OF CNS DISORDERS AND PAIN
[Poster]
Linciano, Pasquale; Sorbi, Claudia; Franchini, Silvia; Tait, Annalisa; Bardoni, Rita; Ronsisvalle, Simone; Denora, Nunzio; Lesniak, Anna; Bujalska-Zadrożny, Magdalena; Pawłowska, Agata; Chichero, Elena; Fossa, Paola; Brasili, Livio
abstract
2019
- Scouting Sigma Receptor Ligands As New Tools For The Treatment Of Neurodegenerative Diseases And Cancer
[Relazione in Atti di Convegno]
Sorbi, C.; Linciano, P.; Tait, A.; Atene, C. G.; Guglielmo, L.; Di Rocco, G.; Ronsisvalle, S.; Denora, N.; Imbriano, C.; Rigillo, G.; Fossa, P.; Cichero, E.; Benassi, L.; Vaschieri, C.; Marocchi, F.; Lanfrancone, M. L.; Brasili, L.; Franchini, S.
abstract
Sigma receptors (Rs) are nowadays recognized as an unique class of membrane receptors divided into two subtypes, R and R. Rs regulate a number of physiological functions and their role has been evaluated in many disorders. Deficits in R are associated with neurodegeneration while their activation may represent a valuable strategy for the treatment of a number of neurodegenerative disorders. Moreover, R is overexpressed in a variety of cancer cells and selective R antagonists are reported to modulate cancer cell viability.1 R are also highly expressed proliferating tumors. R agonists are giving promising results in preclinical studies for the treatment of resistant or hardly treatable tumors and R ligands have been proposed as biomarkers for tumors proliferation.2 However, the identification of potent and selective ligands and the comprehension of the chemical features behind agonism/antagonism still remain a primary challenge in this field. With this aim, following a ligand-based approach, a library of over 120 ligands have been designed and synthesized over the years, by combining different substituted five-membered heterocyclic rings with appropriate R pharmacophoric amines. Compounds were tested for R and R affinity showing Ki values in the micromolar / sub-nanomolar range, with a selectivity mainly shifted toward the R. A detailed SAR, supported by molecular modelling, was drawn up. The intrinsic activity was determined in vivo for the most promising molecules. According to their profile, R agonists were tested for neuroprotection, whereas R antagonists / R agonists for anticancer activity. Preliminary results in SH-SY5Y neuroblastoma cells showed the ability of some compounds to protect neuronal cells from death induced by four toxicity models.
Cell viability assays were performed on different cancer cell lines to assess the anti-proliferative potential of selected molecules. In particular, dose and time dependent treatments were done on prostate cancer cells, which express higher levels of both R and R compared to normal samples. Similarly, we assessed the effect of the compounds on melanoma cells: BS148, a potent and selective R agonist, showed anti-proliferative activity on immortalized and PDX (metastatic melanoma patient-derived xenografts) cell lines.3 Confocal microscopy studies with BS148 fluorescent probe revealed the internalization of BS148 within melanoma cells, with a cytoplasmatic localization, mostly in the perinuclear region, according to R distribution. Finally, to verify whether TMEM97 / R mediates BS148-antiproliferative activity, we stably overexpressed the TMEM97 gene in HeLa cells: TMEM97-Hela were more sensitive to BS148 anti-proliferative activity compared to control cells, which express endogenous R levels.
Taken together, these results support the idea that R is an innovative target in cancer, paving the way for improved tools for cancer diagnosis, monitoring and therapy.
2018
- Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT 1A receptor agonists for CNS disorders and neuropathic pain
[Articolo su rivista]
Franchini, S.; Bencheva, L. I.; Battisti, U. M.; Tait, A.; Sorbi, C.; Fossa, P.; Cichero, E.; Ronsisvalle, S.; Arico, G.; Denora, N.; Iacobazzi, R. M.; Cilia, A.; Pirona, L.; Brasili, L.
abstract
Aim: Targeting 5-HT 1A receptor (5-HT 1A R) as a strategy for CNS disorders and pain control. Methodology: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α 1 -adrenoceptors and 5-HT 1A R by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. Results & conclusion: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT 1A R agonist (pKi = 9.2; pD2 = 8.83; 5-HT 1A /α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.
2017
- Exhaustive CoMFA and CoMSIA analyses around different chemical entities: A ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands
[Articolo su rivista]
Guariento, Sara; Franchini, Silvia; Tonelli, Michele; Fossa, Paola; Sorbi, Claudia; Cichero, Elena; Brasili, Livio
abstract
The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands. (Image presented).
2017
- Structure-Activity Relationship within a new series of σ1 and σ2 receptor ligands: identification of a novel σ2R agonist (BS148) with selective toxicity against metastatic melanoma
[Articolo su rivista]
Franchini, Silvia; Sorbi, Claudia; Battisti, Umberto Maria; Tait, Annalisa; Bencheva, Leda Ivanova; Cichero, Elena; Fossa, Paola; Cilia, Antonio; Prezzavento, Orazio; Ronsisvalle, Simone; Aricò, Giuseppina; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; Magnoni, Cristina; Brasili, Livio
abstract
A new series of spiro-cyclic sigma ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1R; compounds 7b, 15b and 16a were shown to be σ1R agonists, while 16b was proven to be the only σ1R antagonist. Only 16a (BS148) exhibited σ2R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines, whilst not affecting normal human melanocytes. BS148’s anti-proliferative activity suggests a σ2R agonist profile. Further, preliminary investigations indicate that, at least a part, the mechanism of metastatic malignant melanoma cell death induced by BS148 is due to apoptosis.
2017
- Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists
[Articolo su rivista]
Franchini, Silvia; Manasieva, Leda Ivanova; Sorbi, Claudia; Battisti, Umberto M.; Fossa, Paola; Cichero, Elena; Denora, Nunzio; Iacobazzi, Rosa Maria; Cilia, Antonio; Pirona, Lorenza; Ronsisvalle, Simone; Aricò, Giuseppina; Brasili, Livio
abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.
2017
- Synthesis, structural characterization and biological evaluation of 4′-C-methyl- and phenyl-dioxolane pyrimidine and purine nucleosides
[Articolo su rivista]
Franchini, Silvia; Battisti, Umberto M.; Sorbi, Claudia; Tait, Annalisa; Cornia, Andrea; Jeong, Lak Shin; Lee, Sang Kook; Song, Jayoung; Loddo, Roberta; Madeddu, Silvia; Sanna, Giuseppina; Brasili, Livio
abstract
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4′-C-methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
2016
- A homology modelling-driven study leading to the discovery of the first mouse trace amine-associated receptor 5 (TAAR5) antagonists
[Articolo su rivista]
Cichero, Elena; Espinoza, Stefano; Tonelli, Michele; Franchini, Silvia; Gerasimov, Andrey S.; Sorbi, Claudia; Gainetdinov, Raul R.; Brasili, Livio; Fossa, Paola
abstract
Several recent studies have focused on a detailed analysis of the trace amine-associated receptor type 5 (TAAR5) pharmacology, up to now revealing only a limited number of species-specific ligands, which are also active towards other TAAR receptors. In this context, we developed our work on TAAR5 applying a structure-based computational protocol, revolving around homology modeling and virtual screening calculations. In detail, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 model was employed to perform a virtual screening of an in-house library of compounds, including different five-membered ring derivatives, linked to a phenyl ring through a flexible or a rigid basic moiety. The computational protocol applied allowed to select a number of chemical scaffolds that were tested in a biological assay leading to the discovery of the first two mTAAR5 antagonists.
2016
- Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity
[Abstract in Atti di Convegno]
Franchini, Silvia; Sorbi, Claudia; Tait, Annalisa; Benassi, Luisa; Azzoni, Paola; Vaschieri, Crisitina; Pellacani, Giovanni; Prezzavento, Orazio; Ronsisvalle, Simine; Aricò, Giuseppina; Brasili, Livio
abstract
Sigma receptors (σR) have proved to be an attractive pharmacological target for the treatment of several pathologies. In particular, σ1 ligands have been considered to play an important role in the treatment of various neurological disorders, including depression, schizophrenia, neuropathic pain, Alzheimer's and Parkinson’s disease. Moreover, it has been found that σR are involved in the modulation of cellular proliferation and cell death and σ1 antagonists and σ2 agonists may represent useful tools as anticancer and tumor imaging agents.
Recently, we reported that a properly substituted 1,3-dioxolane moiety could be employed as suitable scaffold for developing ligands for both σ1R and σ2R.1 In this work we explore a new set of structural related analogues obtained by combining different substituted spiro-heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified BS148 (1-(1,4-ditiaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperidne) as the most interesting compound of the series, displaying good affinity and selectivity for σ2R .The ability of BS148 to modulate the analgesic effect of the agonist morphine was evaluated in-vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Moreover, BS148 demonstrated to affect the growth (MTT test) of SK-MEL-28 and SK-MEL-2 melanoma cell lines in comparison to siramesine, suggesting an agonistic behavior at σ2R.
The present work represents a new starting point for the design of potential therapeutically useful agents.
2016
- Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives
[Articolo su rivista]
Franchini, Silvia; Battisti, UMBERTO MARIA; Prandi, Adolfo; Tait, Annalisa; Borsari, Chiara; Cichero, Elena; Fossa, Paola; Cilia, Antonio; Prezzavento, Orazio; Ronsisvalle, Simone; Aricò, Giuseppina; Parenti, Carmela; Brasili, Livio
abstract
Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
2016
- Synthesis, biological evaluation and molecular modelling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists
[Abstract in Atti di Convegno]
Sorbi, Claudia; Franchini, Silvia; Manasieva, Leda Ivanova; Battisti, UMBERTO MARIA; Fossa, Paola; Cichero, Elena; Denora, Nunzio; Iacobazzi, Rosa Maria; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio
abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a relevant neurotransmitter both in the central nervous system and in periphery. It mediates several physio-pathological effects through at least 14 receptor subtypes. Among them, the 5-HT1AR subtype has been extensively studied and still represents an attractive target for novel therapeutic uses. Agonists and partial agonists have been initially proven to be effective in anxiety, depression, and psychosis. More recently, they have shown pronounced neuroprotective properties indicating their potential benefit in the treatment of many neurodegenerative disorders, including Parkinson’s disease and cerebral ischemia. Currently, it has been shown that 5-HT1AR is involved at multiple levels in the regulation of nociception and 5-HT1AR agonists may represent a new approach in pain relief therapy. Moreover it was found that 5-HT1AR is implicated in oncogenesis and 5-HT1AR antagonists demonstrated their efficacy in inhibiting the growth of different tumor (prostate, small cell lung). Thus, it is of paramount importance the discovery of more potent and selective 5-HT1AR ligands.
Recently, our research group reported 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) as a potent 5-HT1AR partial agonist (pD2= 8.61). In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested. The results led to the identification of 15, a novel 5-HT1AR partial agonist with a 10-fold improved potency (pD2= 9.58) and about 50 % of enhanced efficacy (Emax= 74%,). MDCKII-MDR1 cells permeability assay predicted the BBB permeability of 15 that also showed a promising neuroprotective activity in vitro
2015
- A New and Versatile Synthesis of 1,3-Dioxan-5-yl-pyrimidine and Purine Nucleoside Analogues
[Articolo su rivista]
Sorbi, Claudia; Prandi, Adolfo; Battisti, UMBERTO MARIA; Franchini, Silvia; Cornia, Andrea; Balzarini, Jan; Jeong, Lak Shin; Lee, Sang Kook; Song, Jayoung; Brasili, Livio
abstract
1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues
were prepared following a new and versatile synthetic strategy. These
analogues were synthesized via nucleophilic addition of the selected
nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving
group in position 5. In particular cis and trans isomers of purine/pyrimidine
nucleosides and their halogenated homologues were obtained.
NMR experiments, carried out on the cis isomers, led to
assignment of an equatorial orientation to the 2-hydroxymethyl group
and axial orientation to the nucleobase in position 5 of the 1,3-dioxane.
The trans isomers showed a diequatorial orientation of these groups.
These assignments were confirmed by X-ray crystallographic studies
2015
- Diastereoselective Synthesis of (1,3-Dioxan-4-yl)pyrimidine and Purin Nucleoside Analogues
[Articolo su rivista]
Battisti, Umberto M.; Sorbi, Claudia; Quotadamo, Antonio; Franchini, Silvia; Tait, Annalisa; Schols, Dominique; Jeong, Lak Shin; Lee, Sang Kook; Song, Jayoung; Brasili, Livio
abstract
(1,3-Dioxan-4-yl)-substituted nucleoside analogues, higher homologues of antiviral and anticancer 1,3-dioxolanes, were prepared from the key intermediate (4-acetoxy-1,3-dioxan-2-yl)methyl benzoate and silylated bases. Glycosylation, carried out under Vorbrüggen conditions in the presence of trimethylsilyltrifluoromethanesulfonate (TMSOTf) as a catalyst, afforded the desired compounds with high stereoselectivity and regioselectivity, with only the desired β-anomeric N-1 pyrimidine and N-9 purin nucleosides being obtained. 1H NMR experiments established that the β-anomers were diequatorial, and this assignment was confirmed by singlecrystal X-ray diffraction. Despite their structural similarities with natural nucleosides, none of the synthesized nucleosides showed antiviral activity.
2015
- Enantiomeric resolution of [(2,2-diphenyl-1,3-dioxolan-4-yl)methyl](2-phenoxyethyl)amine, a potent α1and 5-HT1Areceptor ligand: an in vitro and computational study
[Articolo su rivista]
Franchini, Silvia; Baraldi, Anna Maria; Sorbi, Claudia; Pellati, Federica; Cichero, Elena; Battisti, UMBERTO MARIA; Angeli, Piero; Cilia, Antonio; Brasili, Livio
abstract
In this paper, the enantiomers of (±)-1, previously studied as α1 and 5-HT1A ligands, were prepared both by resolution of the racemate and asymmetric synthesis. The enantiomeric purity and absolute configuration were determined by means of HPLC and polarimetric analysis. Enantiomers were evaluated for in vitro 5-HT1A and α1 receptor affinity by binding and functional assays. Results indicate that the two enantiomers are almost equally potent at 5-HT1A and α1 receptor systems and, contrary to WB 4101, the stereoselectivity is poor. As further support to these experimental findings, molecular docking studies on the two enantiomers of (±)-1 have been performed and a comparison with those obtained for 5-HT1A potent agonist (R)-flesinoxan and α1d antagonist (S)-WB 4101 has been drawn.
2015
- Synthesis and Structure-Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands
[Articolo su rivista]
Corrado, Sandra; Battisti, Umberto M.; Sorbi, Claudia; Tait, Annalisa; Malfacini, Davide; Camarda, Valeria; Calò, Girolamo; Brasili, Livio
abstract
Several spiroxatrine derivatives were synthesized and evaluated as potential NOP receptor ligands. Structural modifications of the 1,4-benzodioxane moiety of spiroxatrine have been the focus of this research project. The structure–activity relationships that emerged indicate that the presence of an H-bond donor group (hydroxyl group) is more favorable for NOP activity when it is positioned a with respect to the CH2 linked to the 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives 4 and 22 show a moderately higher degree of stereoselectivity than trans isomers. In particular, the spiropiperidine derivative cis-4 has submicromolar agonistic activity, and it will be the reference compound for the design and synthesis of new NOP agonists.
2015
- Synthesis of Heteroaryl ortho-Phenoxyethylamines via Suzuki Cross-Coupling: Easy Access to New Potential Scaffolds in Medicinal Chemistry
[Articolo su rivista]
Manasieva, Leda Ivanova; Battisti, UMBERTO MARIA; Prandi, Adolfo; Brasili, Livio; Franchini, Silvia
abstract
Heteroaryl ortho-phenoxyethyl amines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands. Herein we report an efficient, fast and general method for the synthesis of heteroaryl phenoxyethyl amines via Suzuki cross-coupling. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered (thiophene, furan, thiazole, pyrazole, imidazole) or six-membered (pyridine, pyrimidine) heteroaromatic rings for appropriate libraries of ligands. All the compounds presented here have never been synthesized before and a full structural characterization is given.
2014
- 1,4-Dioxolane-triazaspirodecanone derivatives as nociceptin/orphanin FQ receptor ligands
[Articolo su rivista]
Corrado, Sandra; Sorbi, Claudia; Tait, Annalisa; Battisti, Umberto M.; Camarda, Valeria; Malfacini, Davide; Calò, Girolamo; Brasili, Livio
abstract
A series of N-substituted analogs based upon the spiropiperidine core of the lead compound Spiroxatrine was synthesized. In particular, the new compounds were obtained by replacing the benzodioxane moiety of the Spiroxatrine with several 2-substituted 1,3-dioxolanes. Thus the designed derivatives were synthesized and evaluated as possible NOP receptor ligands. As a conclusion of these studies, the new triazaspirodecanone derivatives showed unique and significant SAR as NOP receptor agonists. In particular, the present study demonstrated that 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one portion together with appropriate 1,3-dioxolane substituents could lead to a new promising class of NOP receptor ligands.
2014
- Development, Validation and Application of an LC-MS/MS Bioanalytical Method for the Quantification of GF449, A Novel 5-HT1A Agonist, in Rat Plasma and Brain.
[Articolo su rivista]
Franchini, Silvia; Taddia, Laura; Pinetti, Diego; Carnevale, Gianluca; Brasili, Livio
abstract
We have recently reported a novel class of selective 5-HT1A agonists among which GF449 emerged for its high potency and almost full agonist activity (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 91.6). In order to quantify GF449 in rat plasma and brain, a sensitive LC-MS/MS method was developed and validated. Solid phase extraction (SPE) or a combined protein precipitation SPE permitted an efficient analyte recovery and sample clean-up. Multiple reaction monitoring (MRM) was used to track both GF449 and its internal standard (IS), MM189. GF449 was determined and quantitated to nanomolar concentrations in both plasma and brain matrix (LOQs = 0.0025 nmol/mL). Specificity was ensured using three further MRM qualifier transitions for both analyte and IS. Linearity was found in the range of 0.0025 nmol/mL to 1.00 nmol/mL (R2 = 0.9965) and from 0.0025 nmol/mL to 50 nmol/mL (R2 = 0.9999) for plasma and brain respectively. Intraday trueness ranged from 94.0% to 117.5% for brain and from 93.7% to 108.1% for plasma, while precision values were within 3.0% - 6.7% and 2.5% - 9.2% for plasma and brain respectively. The interday trueness of plasma ranged from 89.6% to 107.7% and the precision values (CV%) ranged from 4.6% to 7.5%. Interday trueness and precision (CV%) of the brain ranged from 94.3% to 101.2% and from 1.6% to 11.5% respectively. The method was validated in accordance with the EMEA guidelines and was successfully applied to plasma and brain samples obtained from rats treated with a 10 mg/kg single oral dose of GF449, thus demonstrating its applicability to pre-clinical pharmacokinetic studies.
2014
- Further insights into the pharmacology of the human Trace Amine-Associated Receptors: discovery of novel ligands for TAAR1 by a virtual screening approach
[Articolo su rivista]
Cichero, 2. E.; Espinoza, S.; Franchini, Silvia; Guariento, S.; Brasili, Livio; Gainetdinov, R. R.; P, . Fossa
abstract
Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-
coupled receptor that is expressed in brain and
periphery and responds to a class of compounds called
trace amines, such as b-phenylethylamine (b-PEA), tyramine,
tryptamine, octopamine. The receptor is known to
have a very rich pharmacology and could be also activated
by different classes of compounds, including
dopaminergic, adrenergic and serotonergic ligands. It is
expected that targeting hTAAR1 could provide a novel
pharmacological approach for several human disorders,
such as schizophrenia, depression, attention deficit
hyperactivity disorder, Parkinson’s disease and metabolic
diseases. Only recently, a small number of selective
hTAAR1 agonists (among which RO5166017 and
T1AM) and antagonist (EPPTB), have been reported in
literature. With the aim to identify new molecular entities
able to act as ligands for this target, we used an homology
model for the hTAAR1 and performed a virtual
screening procedure on an in-house database of compounds.
A number of interesting molecules were
selected and by testing them in an in vitro assay we
found several agonists and one antagonist, with activities
in the low micromolar range. These compounds
could represent the starting point for the development
of more potent and selective TAAR1 ligands.
2014
- Insights into the structure of the Human TAAR5 receptor: a computational study
[Poster]
Cichero, E.; Espinoza, S.; Franchini, Silvia; D'Ursi, P.; Gainetdinov, R. R.; Brasili, Livio; Milanesi, L.; Fossa, P.
abstract
Trace amines (TAs), such as -phenylethylamine (-PEA), tyramine, 3-iodothyronamine (T1AM), octopamine, tryptamine and synephrine, are found at low levels in multiple tissues in the periphery and brain of mammals but their physiological functions remain enigmatic. A recent discovery of a family of rhodopsin-like G protein-coupled receptors (GPCRs), defined as Trace Amine-Associated Receptors (TAARs), has provided an opportunity to explore the roles of TAs and their receptors in physiology and disease. The human TAAR family consists of six genes and three pseudogenes and characterized by location on a single chromosome, high overall sequence homology to monoamine receptors, and the presence of a TAAR-specific peptide fingerprint motif with the seventh transmembrane domain that is not found in all other known GPCRs. It is believed that the TAAR family most likely evolved from a common ancestor gene sharing closest similarity to the human gene encoding serotonin 5-HT4 receptor via a series of gene duplication events [1].
Human and murine TAAR1 (h/mTAAR1) are expressed in a variety of tissues including brain, stomach, kidney, lung and intestine, but not in the olfactory epithelium (OE). On the contrary, with the exception of hTAAR1, all human TAARs proved to be exclusively expressed in small areas of olfactory sensory neurons (OSNs) in the OE [2].
Recently, several research groups focused their efforts to investigate TAAR5 receptor pharmacology and, up to now, only one compound has been proved to act as TAAR5 agonist: trimethylamine (TMA) [3]. Up to now, being TAs able to interact with all the TAARs receptor, selective hTAAR5 ligands are still unknown. On the other hand, trimethylamine proved to be the only TAAR5 agonist described in literature. In this context, with the aim of identifying specific and selective ligands for TAAR5, we built an homology model of the receptor, which first of all allowed us to explore which different amino acids can be involved in the binding of hTAAR5 ligands. Furthermore, we used the derived model as a tool for virtual screening analyses. In particular, we focused our attention on an in-house database of compounds, which already proved to be active as 5HT1A ligands. The selected database includes a series of aryloxyalchylamines and N1-arylpiperazines obtained by combining 30 different scaffolds bearing a flexible or a rigid basic core. The scaffolds were chosen within a series of substituted 1,3-dioxolane, 1,3-oxathiolane, 1,3-dithiolane, spiro-dioxolane, 1,4-dioxane, tetrahydrofuran, cyclopentanone-, cyclopentanol based compounds, previously discussed and published by some of us [4 and literature cited therein]. Following this procedure, we identified one compound (1) which proved to be a selective TAAR5 antagonist.
2014
- Pyrrolidine Derivatives as New Ligands for 5-HT1A Receptors
[Abstract in Atti di Convegno]
Sorbi, Claudia; Tait, Annalisa; Brasili, Livio
abstract
Our research group has long been involved in the development of new 5-HT1A selective ligands and 1,3-dioxolane derivatives bearing a phenoxyethylamine basic portion in position 4 were reported1. They were shown to have interesting 5-HT1A agonist activity accompanied by a good affinity, even if a certain alpha1 affinity was still present.
5-HT1A agonists and partial agonists have proved useful in the treatment of neuropsychiatric disorders such as anxiety and depression, to prevent neurodegeneration and for their antinociceptive activity2,3.
On this basis and with the aim to improve 5-HT1A affinity and selectivity, compound A derivatives have been synthesized. A frozen structure of the ethylamine portion characterizes the new ligand and this variation4 with respect to the lead A has been designed in order to decrease the flexibility of this part of the molecule (figure 1). Stereospecific synthesis has been planned to give the desired four enantiomers (figure 1) so that it has been evaluated:
1. the effect on 5-HT1A affinity of the molecular rigidity provided by pyrrolidine core in comparison to that of the lead compound A;
2. stereoisomeric preferences for the receptor interaction.
Several reactions and different synthetic schemes have been followed to obtained these four stereoisomers with good yield and a process optimization has been pursued.
Structural characterization by NMR and mass (Q-TOF) analysis have been performed on the final compounds together with their optical purity determination.
2014
- Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors
[Articolo su rivista]
Franchini, Silvia; Battisti, UMBERTO MARIA; Baraldi, Anna Maria; Prandi, Adolfo; Fossa, Paola; Cichero, Elena; Tait, Annalisa; Sorbi, Claudia; Marucci, Gabriella; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio
abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α<alpha>1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α<alpha>1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α<alpha>1 or 5-HT1AR ligands.
2014
- Synthesis, enantiomeric separation and docking studies of spiropiperidine analogues as ligands of the nociceptin/orphanin FQ receptor
[Articolo su rivista]
Battisti, Umberto M.; Corrado, Sandra; Sorbi, Claudia; Cornia, Andrea; Tait, Annalisa; Malfacini, Davide; Cerlesi, Maria Camilla; Calò, Girolamo; Brasili, Livio
abstract
A series of triazospirodecanone derivatives were synthesized as potential NOP ligands. 8-(Chroman-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (4) and its 5-fluoro analogue (18) proved to be active as agonists with EC50 values in the submicromolar range. Single enantiomers of compound 4 were separated and tested as NOP agonists; the eutomer R-(+)-4 showed a pEC50 of 7.34. Finally docking studies were performed on the NOP receptor to identify the most significant stereospecific interactions.
2014
- Transacetalization of Acetals with Butane-1,2,4-triol Using Cobalt(II) Chloride and Chlorotrimethylsilane
[Articolo su rivista]
Battisti, UMBERTO MARIA; Sorbi, Claudia; Franchini, Silvia; Tait, Annalisa; Brasili, Livio
abstract
Transacetalization of acetals with 1,2,4-butanetriol was carried out using cobalt(II) chloride and chlorotrimethylsilane as catalysts. The reaction occurs under mild conditions in acetonitrile with a short reaction times. The synergic effect of the two Lewis acids catalyzes the conversion of butane-1,2,4-triol into (2-alkyl or 2-aryl-1,3-dioxan-4-yl)methanol derivatives with high regiospecificity and diasteroselectivity.
2013
- Insights into the structure and pharmacology of Trace Amine-Associated Receptor 1 (TAAR1), a new target for medicinal chemistry
[Poster]
Cichero, E.; Espinoza, S.; Franchini, Silvia; Gainetdinov, R. R.; Brasili, Livio; P., Fossa
abstract
Trace amines (TAs), such as b-phenylethylamine (b-PEA), tyramine, 3-iodothyronamine (T1AM), octopamine, tryptamine and synephrine, are found at low levels in multiple tissues in the periphery and brain of mammals but their physiological functions remain enigmatic. A recent discovery of a family of rhodopsin-like G protein-coupled receptors (GPCRs), defined as Trace Amine-Associated Receptors (TAARs), has provided an opportunity to explore the roles of TAs and their receptors in physiology and disease. The human TAAR family consists of six genes and three pseudogenes and characterized by location on a single chromosome, high overall sequence homology to monoamine receptors, and the presence of a TAAR-specific peptide fingerprint motif with the seventh transmembrane domain that is not found in all other known GPCRs. It is believed that the TAAR family most likely evolved from a common ancestor gene sharing closest similarity to the human gene encoding serotonin 5-HT4 receptor via a series of gene duplication events [1]. The most studied Trace Amine-Associated Receptor 1 (TAAR1) signals via the Gs protein/adenylyl cyclase system and could be activated not only by TAs, but also by amphetamine derivatives, monoamine metabolites, iodothyronamines, ergolines as well as certain adrenergic and serotonergic drugs [2, 3]. Until recently, the lack of selective ligands has rendered a challenging task the exploration of TAAR1 biological functions. Only in 2010-2011, Hoener and co-workers have reported the identification of first selective TAAR1 ligands [4] with selective TAAR1 agonist RO5166017 being much more potent than the trace amine -PEA. TAAR1 is expressed in several brain regions. Accumulating evidence indicates that TAAR1 is involved in the modulation of dopaminergic and serotonergic systems, making this receptor as a promising novel target for drug discovery to manage monoaminergic disorders such as schizophrenia, depression, attention deficit hyperactivity disorders (ADHD) and Parkinson’s disease [5]. Up to now, experimental data highlighting the hTAAR1 key residues responsible for ligand recognition are not available. The aim of this study was to perform an “in silico” investigation focused to explore which different amino acid residues could be involved in the binding of hTAAR1 ligands, so as to have a useful tool for the virtual identification of new chemical entities acting on this protein.
2013
- Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies
[Articolo su rivista]
Cichero, Elena; Espinoza, Stefano; Gainetdinov, Raul R; Brasili, Livio; Fossa, Paola
abstract
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.
2012
- 5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors
[Articolo su rivista]
Umberto M., Battisti; Krzysztof, Jozwiak; Cannazza, Giuseppe; Puja, Giulia; Gabriella, Stocca; Braghiroli, Daniela; Parenti, Carlo; Brasili, Livio; Marina M., Carrozzo; Cinzia, Citti; Luigino, Troisi
abstract
The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3-dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood–brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPAr-positive modulator candidates.
2012
- Efficient synthesis of 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de] phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij] thieno[2,3-c]quinoline 4,4-dioxide
[Articolo su rivista]
Battisti, UMBERTO MARIA; Carrozzo, Marina Maria; Cannazza, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Brasili, Livio; Cinzia, Citti; Luigino, Troisi
abstract
A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.
2012
- Synthesis of 5-Methyl-1,3-oxathiolane-based Nucleoside Analogues as Potential Antiviral Agents
[Articolo su rivista]
Franchini, Silvia; Tait, Annalisa; Sorbi, Claudia; Brasili, Livio
abstract
A series of 1,3-oxathiolane-based nucleoside analogues 5-methyl substituted was synthesized and tested as potential antiviral agents. Structural characterization and C2-C4 / C2-C5 relative stereochemistry assignments were performed by NMR experiments. All tested isomers were found to be inactive and cytotoxic.
2012
- Synthesis, Biological Evaluation and Docking Studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at Adrenergic alpha1- and Serotonine 5-HT1A receptors
[Articolo su rivista]
Prandi, Adolfo; Franchini, Silvia; L., Ivanova Manasieva; P., Fossa; E., Cichero; G., Marucci; M., Buccioni; A., Cilia; L., Pirona; Brasili, Livio
abstract
A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT1A receptors and alpha1-adrenoceptor subtypes was measured binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone or cyclopentanol mojety leads to an overall reduction of in vitro affinity at the alpha1-adrenoceptor while both potency and efficacy were increased at the 5-HT1A receptor. A significant improvement of 5-HT1A/alpha1 selectivity was observed in some of the cyclopentanol derivatives synthesised (4a cis, 4c cis and trans). Compounds 2a and 4c cis emerged as novel and interesting 5-HT1A receptor antagonist (pKi = 8.70) and a 5-HT1A receptor partial agonist (pKi = 9.25, pD2= 9.03, Emax= 47%, 5-HT1A/alpha1a= 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT1A agonism/antagonism activity.
2012
- Synthesis, structural characterization and pharmacological evaluation of spiroxatrine analogs as potential nociceptin/orphanin FQ receptor ligands
[Abstract in Atti di Convegno]
Corrado, Sandra; Battisti, Umberto; Sorbi, Claudia; Malfacini, Davide; Calò, Girolamo; Brasili, Livio; Tait, Annalisa
abstract
The nociceptin/Orphanin FQ (N/OFQ) peptide (NOP) receptor is a G protein-coupled receptor with a high degree of structural homology (~ 60%) to the classical opioid receptors μ, δ and κ. The interaction between NOPand its endogenous agonist N/OFQ plays a key role in pain transmission, among other biological functions. Therefore, this system opened a new option for the treatment of acute and chronic pain possibly by generating drugs with a lower side effect profile.The confirmed affinity towards NOP receptor of the α2 adrenergic and 5-HT1A partial agonist spiroxatrine (Ki= 127 nM) has led us to the synthesis of a series of novel and optimized analogs based upon the spiropiperidinecore, in order to perform preliminarySAR studies.
2011
- Evaluation of stereo and chemical stability of chiral compounds
[Articolo su rivista]
Cannazza, Giuseppe; Battisti, UMBERTO MARIA; Carrozzo, Marina Maria; Brasili, Livio; Braghiroli, Daniela; Parenti, Carlo
abstract
A stopped-flow bidimensional recycle HPLC (sf-BD-rHPLC) configuration has been used to investigate simultaneously the stereo and chemical stability of labile chiral compounds. The single enantiomers of a racemate can be separated on chiral column (first dimension) and each one can be trapped in the achiral column (second dimension) that works as reactor.By filling the achiral column with the appropriate aqueous buffers it is possible to evaluate the stability of the trapped enantiomer toward aqueous buffer itself. It was possible to recycle the reaction products formed in the chiral column (first dimension) where they are separated by a second six valve port. The reaction rate constants were calculated for the different processes occurred in the achiral column by means of corresponding peak areas. The method was applied to a pharmacological active compound: (±)7-chloro-5-ethyl-3-methyl-3,4-dihydro-2H-benzo[1,2,4]thiadiazine 1,1-dioxide ((±)-1) to evaluate enantiostability and hydrolysis in conditions similar to those of biological fluid. A classical batchwise kinetic method was used to calculate rate constants of hydrolysis and enantiomerization at the same temperature and in the same solvents used in sf-BD-rHPLC. The good agreement of the results obtained validate the novel procedure developed. Furthermore, the results generated off-line were used to determine the influence of solvents on the racemization of (±)-1.
2011
- Synthesis and pharmacological evaluation of Spiroxatrine derivatives as potential ligands for NOP receptor
[Abstract in Atti di Convegno]
Corrado, Sandra; Sorbi, Claudia; Manasieva, Leda; Camarda, Valeria; Calò, Girolamo; Brasili, Livio; Tait, Annalisa
abstract
Gli Atti del XXIV Congresso Nazionale della Società Chimica Italiana raccolgono gli abstract degli otre 1000 contributi scientifici del Congresso svoltosi a Lecce dall'11 al 16 settembre 2011. Il Congresso si articola in una sessione comune, con lectures tenute da ospiti prestigiosi (una menzione particolare meritano i 2 Nobel per la Chimica Jean-Marie Lehn e Kurt Wuthrich) e ben 12 sessioni parallele delle singole divisioni. Gli Atti contengono anche le schede dei docenti che saranno insigniti delle Medaglie della Società Chimica Italiana.
2011
- Synthesis and structural characterization of spiroxatrine derivatives as potential non-peptide ligands for NOP receptor
[Abstract in Atti di Convegno]
Corrado, Sandra; Sorbi, Claudia; Brasili, Livio; Tait, Annalisa
abstract
Nociceptin or orphanin FQ peptide (N/OFQ) was identified in 1995 as the endogenous ligand for the opioid receptor ORL-1, actually denominated NOP, a fourth member of the classical μ, δ and κ opioid receptors family. N/OFQ-NOP system is implicated in several biological functions, such as in pain modulation. Therefore, NOP receptor represents an interesting target for the development of new therapeutical agentsagainst the acute cancer pain. On the basis of the confirmed affinity towards NOP receptor of the alpha2 adrenergic and 5-HT1A partial agonist spiroxatrine(Ki= 127 nM), we focused our attention on the design, synthesis and characterization of novel NOP receptor ligands with a spiropiperidine portion. The aim was to study the effects of some structural modifications on the 1,4-benzodioxane moiety ofspiroxatrine. In particular, we carried out: 1) isosteric replacement of C8 with a nitrogen atom; 2) disconnection of 1-8a and 4-4a bonds of spiroxatrine and of its nitrogen isosteres to give derivatives with a primary or a secondary alcoholic group respectively (2-5); 3) replacement of 1,4-benzodioxane moiety of spiroxatrine with a 1-benzhydryloxy-propan-2-ol and 2-benzhydryloxy-propan-1-ol moiety in order to increase the steric hindrance (6-7). Retrosynthetic strategies for compounds 1-7 are shown in the following schemes. Compounds 1-7 will be subjected to biological activity assays.
2010
- 1,3-Dioxolane-Based Ligands Incorporating a Lactam or Imide moiety: Structure-Affinity/Activity Relationship at alpha1–Adrenoceptor subtypes and at 5-HT1A Receptors
[Articolo su rivista]
Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; Sorbi, Claudia; Tait, Annalisa; M., Buccioni; G., Marucci; A., Cilia; L., Pirona; P., Fossa; E., Cichero; Brasili, Livio
abstract
A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolanederivative 1, previously shown to be a selective alpha1a(A)/alpha1d(D)-adrenoceptor subtype antagonist, overalpha1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha1/ 5-HT1A selectivity is observed, mainly due to the increase in 5-HT1A affinity. In functional experiments lactam derivatives seems to favour 5-HT1A receptor antagonism (pKb =7.20-7.80) and alpha1B-adrenoceptor antagonist selectivity (alpha1B/alpha1A and alpha1B/alpha1D of about 10-fold). Themost interesting of the various imide derivatives is compound 7t, which is a selective alpha1Dadrenoceptorantagonist (pKb = 8.1 and alpha1D/alpha1A and alpha1D/alpha1B selectivity ratios of 16 and 11respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 = 7.98, Emax = 60%).].Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based onmolecular docking studies was used to elucidate the atomic details of the 5HT1A /agonist and 5HT1A/antagonist interaction.
2010
- Discovery of a new 5-HT1A receptor agonist, acting ‘in vivo’ in a rat model of anxiety and depression
[Abstract in Atti di Convegno]
Franchini, Silvia; Sorbi, Claudia; Manasieva, LEDA IVANOVAA; Baraldi, Anna Maria; Prandi, Adolfo; Zanoli, Paola; Carnevale, Gianluca; DI VIESTI, Vittoria; Cilia, A; Pirona, L; Brasili, Livio
abstract
Not available
2010
- Discovery of a new series of 5-HT1A receptor agonists
[Articolo su rivista]
Franchini, Silvia; Prandi, Adolfo; Sorbi, Claudia; Tait, Annalisa; Annamaria, Baraldi; Piero, Angeli; Michela, Buccioni; Antonio, Cilia; Elena, Poggesi; Paola, Fossa; Brasili, Livio
abstract
Starting from compounds previously disclosed as 1-adrenoceptor antagonists which were also found to bind to 5-HT1A receptor, in the attempt to separate the two activities, a new series of 5-HT1A receptor agonist was identified. They were shown to have high potency and/or high selectivity. Among them compound 13 that combine high selectivity (5-HT1A/1= 151) and good agonist potency (pD2= 7.82; Emax=76) turned out to be the most interesting of the series.
2010
- Heteroarylphenoxyethyl amine as selective 5-HT1A receptor ligands: synthesis and structure-activity ralationship studies.
[Abstract in Atti di Convegno]
Manasieva, LEDA IVANOVAA; Baraldi, Anna Maria; Franchini, Silvia; P., Fossa; E., Cichero; A., Cilia; E., Poggesi; Tait, Annalisa; Brasili, Livio
abstract
not available
2009
- (2,2-Diphenyl-[1,3]oxathiolan-5-ylmethyl)-(3-phenylpropyl)-amine: a Potent and Selective 5-HT1A Receptor Agonist
[Articolo su rivista]
Franchini, Silvia; Tait, Annalisa; Prandi, Adolfo; Sorbi, Claudia; Gallesi, Rossella; M., Buccioni; G., Marucci; C., De Stefani; A., Cilia; Brasili, Livio
abstract
Starting from compound 1, a previously reported a1D-adrenoceptorsantagonist, a new series of ligands acting at 5-HT1A serotoninreceptor were identified through simple structure modifications.Among them (2,2-diphenyl-[1,3]oxathiolan-5-yl-methyl)-(3-phenylpropyl)amine (19) exhibits outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5-HT1A/a1D>150), and representsan as yet unidentified 5-HT1A agonist scaffold.
2009
- 1,3-Dioxolane-Based Ligands as Rigid Analogues ofNaftopidil: Structure–Affinity/Activity Relationships at a1and 5-HT1A Receptors
[Articolo su rivista]
Sorbi, Claudia; Franchini, Silvia; Tait, Annalisa; Prandi, Adolfo; Gallesi, Rossella; P., Angeli; G., Marucci; L., Pirona; E., Poggesi; Brasili, Livio
abstract
Conformational restriction of naftopidil proved to be compatiblewith binding at a1 adrenoceptor subtypes and 5-HT receptor1A (5-HT1A), and led to the discovery of a new class of ligandswith a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane)structure. Compound 7 shows the highest affinity toward a1aand a1d adrenoceptor subtypes (pKia1a=9.58, pKia1d=9.09)and selectivity over 5-HT1A receptors (a1a/5-HT1A=100, a1d/5-HT1A=26). In functional experiments it behaves as a potentcompetitive a1a and a1d adrenoceptor antagonist (pKba1A=8.24, pKba1D=8.14), whereas at 5-HT1A receptors it is a potentpartial agonist (pD2=8.30). Compounds 8 and 10 display highaffinity (pKi=8.29 and 8.26, respectively) and selectivity for 5-HT1A (5-HT1A/a1=18 and 10). In functional experiments at the5-HT1A receptor, compound 8 appears to be neutral antagonist(pKb=7.29), whereas compound 10 is a partial agonist (pD2=6.27). Therefore, 1,3-dioxolane-based ligands are a versatileclass of compounds useful for the development of more selectiveligands for one (a1) or the other (5-HT1A) receptor system.
2009
- 1-(1,4-Dioxa-spiro[4.5]dec-2ylmethyl)-4-(2-methoxy-phenyl)-piperazine: SAR at alpha1 and 5-HT1A Receptors.
[Abstract in Atti di Convegno]
Baraldi, Anna Maria; Franchini, Silvia; Manasieva, LEDA IVANOVAA; A., Cilia; E., Poggesi; Brasili, Livio
abstract
Not Available
2009
- Structure Activity Relationships at 5-HT1A receptors within a novel series of 4-alkyl-1-arylpiperazine derivatives
[Abstract in Atti di Convegno]
Baraldi, Anna Maria; Franchini, Silvia; Manasieva, LEDA IVANOVAA; Sorbi, Claudia; A., Cilia; E., Poggesi; Brasili, Livio
abstract
...
2009
- The XIXth National Meeting on Medicinal Chemistry: Verona, Italy
[Relazione in Atti di Convegno]
Brasili, Livio; D., Donati; L., Mosti
abstract
Not Available
2008
- Investigation within a new series of heterocyclic biaryl piperazines acting at 5-HT1A serotoninergic receptors
[Abstract in Atti di Convegno]
Franchini, Silvia; M., Borriello; Prandi, Adolfo; Baraldi, Anna Maria; R., Di Fabio; Brasili, Livio
abstract
Not available
2007
- Synthesis and pharmacological evaluation of 1-benzylpiperazine and 4-benzylpiperidine as potent sigma ligands.
[Abstract in Atti di Convegno]
Baraldi, Anna Maria; Franchini, Silvia; Prandi, Adolfo; O., Prezzavento; G., Ronsisvalle; L., Pirona; Brasili, Livio
abstract
It is now well established that sigma receptors are an independent class of receptors expressed in peripheral organs and in the central nervous system. There are at least two identified subtypes, namely sigma1 and sigma2, with distinct functional roles and different pharmacological characteristics. On the basis of their neuroregulative and neuropotective functions sigma1 agents could be potentially used for the treatment of depression and psychiatric disorders. The finding of high concentration of sigma2 receptors in neuronal and non-neuronal tumor cell lines provides evidence of a possible role in anticancer therapy. A variety of chemically unrelated compounds is able to bind sigma receptors, however only few bind with high affinity and selectivity to sigma receptor subtypes. This situation has given new impulse to medicinal chemists for the search of new and more selective ligands.We have recently reported that substituted 1-benzylpiperazine and 4-benzylpiperidine derivatives were shown to be high-affinity sigma ligands (Ki in the nanomolar range) with a slight preference for sigma1 over sigma2 receptors1-2. With the aim to improve sigma1/sigma2 selectivity we have studied the effect of some substitutions of the oxygen atoms on the 1,3-dioxolane ring by synthesizing 1,3-oxathiolane, 1,3-dithiolane, tetrahydro-furan, cyclopentanone and cyclopentanol derivatives as depicted below. A spiro derivative was additionally prepared and tested to study the influence of the two aromatic rings on receptor affinity. The preliminary pharmacological results show a significant improvement of sigma1 selectivity for compound A. Structure-activity relationship will be extensively discussed during the congress.
2006
- Structure Activity Relationship at 5-HT1A receptors within a novel series of spiro-1,3-Dioxolane-based ligands
[Abstract in Atti di Convegno]
Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; P., Angeli; G., Marucci; M., Buccioni; A., Leonardi; E., Poggesi; G., Motta; Brasili, Livio
abstract
...
2006
- Synthesis and biological evaluations of 4-alkyl-1-Arylpiperazine derivatives: SAR at 5-HT1A and 1 –Adrenoreceptor
[Abstract in Atti di Convegno]
Franchini, Silvia; Prandi, Adolfo; Baraldi, Anna Maria; G., Marucci; M., Buccioni; P., Angeli; A., Leonardi; E., Poggesi; G., Motta; Brasili, Livio
abstract
...
2005
- 1,2,4-Benzothiadiazine derivatives as alpha(1) and 5-HT1A receptor ligands
[Articolo su rivista]
Tait, Annalisa; Luppi, Amedeo; Franchini, Silvia; E., Preziosi; Parenti, Carlo; M., Buccioni; G., Marucci; A., Leonardi; E., Poggesi; Brasili, Livio
abstract
A series of new 1,2,4-benzothiadiazine derivatives with an arylpiperazine mojety linked at position 3 of the heterocyclic ring were synthesized and assessed for their pharmacological profiles at alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) by functional experiments and by in vitro binding studies at human cloned 5-HT1A receptor. Compound I was identified as a novel (alpha(1D) antagonist (pK(b)alpha(1D) = 7.59; alpha(1D)/alpha(1A) > 389; alpha(1D)/alpha(1B) = 135) with high selectivity over 5-HT1A receptor (5-HT1A/alpha(1D) < 0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT1A receptor ligand, highly selective over alpha(1D)-adrenoceptor subtype (pK(i)5-HT1A = 8.04; 5-HT1A/alpha(1D) = 1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT1A receptor (E-max = 23, pD(2) = 6.92).
2005
- Benzothiadiazine derivatives as 1 and 5-HT1A receptor ligands.
[Abstract in Atti di Convegno]
Tait, Annalisa; Franchini, Silvia; M., Buccioni; G., Marucci; A., Leonardi; E., Poggesi; Brasili, Livio
abstract
...
2005
- SAR at alpha1-adrenoceptor subtypes and 5-HT1A receptors within a novel series of 1,3-Dioxolane-based ligands.
[Poster]
Brasili, Livio; Franchini, Silvia; Prandi, A.; Tait, A.; Angeli, P.; Marucci, G.; Leonardi, A.; Poggesi, E.
abstract
Receptors for adrenaline/noradrenaline and serotonine (5-HT) are an heterogeneous population, ubiquitously distributed in the whole organism. These receptors belong to the G-protein-coupled receptor (GPCR) superfamily which represent the molecular target for over 45% of all marked drugs.
We have recently reported on a new series of 1 adrenergic antagonists bearing a 1,3-dioxolane structure among which compounds A is outstanding in terms of affinity and selectivity [1]. Binding studies have demonstrated that these molecules bind also with good affinity at 5-HT1A receptors.
In order to improve activity and selectivity we have studied the effect of the introduction of lactame and imide moieties as depicted below. The results of the functional and binding studies at 1-adrenoceptor subtypes as well as the binding studies at human cloned 5-HT1A receptors will be discussed during the congress.
2005
- Second Joint Italian-Swiss Meeting on Medicinal Chemistry , Italy, Modena 19-20 February 2005.
[Relazione in Atti di Convegno]
Brasili, Livio; Benvenuti, Stefania; Costantino, Luca; Costi, Maria Paola; Philipp, Floersheim; Franchini, Silvia; Gamberini, Gianfranco; Parenti, Carlo; Rastelli, Giulio; Rustichelli, Cecilia; Tait, Annalisa; Tondi, Donatella
abstract
The Second Joint Italian-Swiss Meeting on Medicinal Chemistry (ITCHMC2005) was held in Modena, (Italy) from September 12 to 16, 2005, under the auspices of the European Federation of Medicinal Chemistry (EFMC).This year, the annual meeting of the Division of Medicinal Chemistry of the Italian Chemical Society was co-organized with the Division for Medicinal Chemistry of the Swiss Chemical Society and it followed the first, successful one held in Torino in September 1997. This important event in the field of medicinal chemistry brought together scientists from both academia and industry to discuss different aspects of modern medicinal chemistry. Top-ranking scientists from medicinal chemistry and clinical development had the opportunity to meet and discuss the following topics: Carbohydrate Chemistry in Drug Design, Nuclear Receptors, Progress in Design and Development of Protease Inhibitors, Progress in Oncology Research and finally, Pain and Neurodegenerative Diseases.IntroductionThe conference was attended by 300 scientists from 13 countries, with most of the participants from Italy and Switzerland. The meeting allowed an extensive exchange of information and widespread networking. Of the 134 posters on display, 19 were selected for short oral presentations and two were selected for the Farminidustria awards. The meeeting was organized in six sessions with 6 Plenary (PL), 16 Main Lectures (ML) and 19 short communications (SC).The scientific sessions were held at the Forum Guido Monzani, a modern complex with multifunctional facilities; the opening ceremony took place at Accadenia Militare di Modena, housed in the seventeenth century Palazzo Ducale.Modena, city of art, culture and prosperous economy, offered an exciting background for stimulating scientific interactions. Participants were mainly from academia and other research centers together with 46 pharmaceutical companies; among them, six presented their work, namely Novartis Basel , Roche Basel, Novartis East Hannover USA, IRBM Pomezia Italy, Santhera Pharmaceutical AG, Heidelberg, GlaxoSmithKline (GSK) Verona, S-IN Soluzioni Informatiche, Vicenza. The areas covered by the meeting were advanced medicinal chemistry including computational chemistry, established drug targets, libraries and screens, inhibitor design and clinical advances. There were two poster sessions, with presentations given mainly by young scientists.
2005
- Synthesis and antimuscarinic activity of derivatives of 2-substituted-1,3-dioxolanes
[Articolo su rivista]
Marucci, G; Angeli, P; Brasili, Livio; Buccioni, M; Giardinà, D; Gulini, U; Piergentili, A; Sagratini, G; Franchini, Silvia
abstract
Geometric cis, traits isomers, derivatives of 2-substituted-1,3-dioxolanes and 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabbit vas deferens (putative M-1), guinea-pig heart (M-2) and guinea-pig ileum (M-3). The effect of the replacement of a trimethylammonium group with a dimethylsulfonium in the two rings was also evaluated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.
2005
- Synthesis and structure-activity relationships of 1-aralkyl-4- benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent σ ligands
[Articolo su rivista]
Costantino, Luca; Gandolfi, Francesca; Sorbi, Claudia; Franchini, Silvia; Prezzavento, O; Vittorio, F; Ronsisvalle, G; Leopardi, A; Poggesi, E; Brasili, Livio
abstract
In the attempt to define more accurately structure-affinity relationships for ó1 and ó2 ligands,we synthesized and tested on ó subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine,in which the effect of modifications on the aralkyl moiety was studied in a systematicway. The affinity of the compounds here described varied to a great extent, with a ó2/ó1selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative tobind to ó1 receptors in a different way than piperidines, we synthesized and tested a series ofpiperazine compounds; the comparison of their affinity with that of the correspondingpiperidines strongly supports the possibility of a different binding mode. While the compoundshere described are on the whole selective for ó vs serotonin 5-HT1A and dopamine D2 receptors,9aa, 9ba and 9ab possess a remarkable affinity for both ó and 5-HT1A receptors, with Ki inthe nanomolar range, and are selective with respect to D2 receptors. They displayed also apartial agonist profile in a human 5-HT1A [35S]GTPçS binding assay, suggesting their potentialuse as atypical antipsychotic agents.
2004
- 1,3-Diossolani e analoghi aperti come nuovi ligandi per il recettore Sigma
[Abstract in Atti di Convegno]
Franchini, Silvia; Prandi, Adolfo; Paini, Silvia; Paini, Stefania; O., Prezzavento; G., Ronsisvalle; Brasili, Livio
abstract
...
2004
- Derivati 1,3-diossanici come ligandi alpha1 adrenergici e 5-HT1A serotoninergici.
[Relazione in Atti di Convegno]
Franchini, Silvia; Prandi, Adolfo; Gandolfi, Francesca; P., Angeli; G., Marucci; A., Leonardi; E., Poggesi; Brasili, Livio
abstract
I recettori adrenergici alpha1 rappresentano una popolazione eterogenea e, dei tre sottotipi recettoriali farmacologicamente caratterizzati, il recettore α1A ha ricevuto la maggiore attenzione quale potenziale target per il trattamento dell’ipertrofia prostatica benigna (BPH). Mentre un numero consistente di antagonisti α1A sono attualmente disponibili, ligandi per i sottotipi α1B e α1D sono in numero limitato e posseggono uno scarso grado di selettività. Anche i recettori per la serotonina (5-HT) costituiscono una popolazione eterogenea e mostrano un elevato grado di omologia strutturale con i recettori alpha1 adrenergici. Questa e’ una delle ragioni che rende tuttora difficile la realizzazione di ligandi selettivi. Recentemente il nostro gruppo di ricerca ha individuato una nuova classe di antagonisti alpha1 adrenergici a struttura 1,3-diossolanica di cui i composti 1 e 2 rappresentano i termini più significativi della serie1. Studi di binding hanno dimostrato che questi composti si legano anche ai recettori 5-HT1A (1: Ki= 0.6 nM; 2: Ki=3.5 nM). In questo studio sono presentate le variazioni strutturali apportate ai composti lead 1 e 2 allo scopo di ottimizzare attività e selettività mediante:-omologazione dell’anello 1,3-diossolanico ad anello 1,3-diossanico -successiva variazione della distanza tra l’atomo di azoto e la porzione 2,2 difenilica, così come riportato nello schema seguente. I risultati farmacologici preliminari indicano che i nuovi composti si legano con buone affinità ai due sistemi recettoriali e che opportune modifiche strutturali indirizzano la selettività verso il recettore 5-HT1A, con una elevata attività di agonismo parziale.
2004
- I-1 imidazoline receptor-mediated effects on apoptotic processes in PC12 cells
[Articolo su rivista]
Dupuy, L; Urosevic, D; Greney, H; Quaglia, W; Pigini, M; Brasili, Livio; Dontenwill, M; Bousquet, P.
abstract
No Abstract
2004
- Pharmacophore Development and 3D-QSAR Study of I1 Imidazoline Binding Site Ligands
[Articolo su rivista]
O., Nicolotti; A., Carotti; A., Carrieri; M., Pigini; F., Gentili; Brasili, Livio; M., Giannella; W., Quaglia; A., Piergentili; P., Bousquet; M., Dontenwill
abstract
Binding affinities at I-1 and I-2 Imidazoline Binding Sites (IBS) of a number of properly substituted imidazoline, oxazoline and pyrroline ligands were studied through an integrated modelling approach based on a coordinated application of 2D- (MGZ) and 3D-QSAR (CoMFA-and GRID-GOLPE) analyses and on the development of a quantitative pharmacophore (HypoGen). Congruent and significant cross-validated 2D and 3D correlations, having promising predictive ability, indicated that electrostatic and steric interactions differently modulate the binding affinities at I-1/I-2 IBS. Stereoselective interactions of chiral alpha or beta substituted imidazolines, leading to diverse I-1/I-2 binding affinities and selectivities, were correctly predicted by the models. Slightly different pharmacophore features were detected by means of Hypogen for I-1 and I-2-IBS ligands.
2004
- Relazioni struttura-attività in una nuova serie di ligandi alpha1-adrenergici e 5-HT1A serotoninergici a struttura 2,2-difenil-[1,3]diossolanica
[Abstract in Atti di Convegno]
Prandi, Adolfo; Franchini, Silvia; Sorbi, Claudia; Cancian, Laura; P., Angeli; G., Marucci; A., Leonardi; E., Poggesi; Brasili, Livio
abstract
...
2004
- Ring opening effect at alpha1-adrenoceptor subtypes and 5-HT1A receptors within a novel class of 1,3-Dioxolane-based ligands
[Abstract in Rivista]
Brasili, Livio; Franchini, Silvia; Prandi, Adolfo; P., Angeli; G., Marucci; M., Buccioni; A., Leonardi; E., Poggesi
abstract
N/A
2004
- Risoluzione della miscela racemica del (±)-(2,2-difenil-[1,3]diossolan-4-ilmetil)-(2-fenossi-etil) ammina, potente antagonista alpha1 adrenergico,
[Abstract in Atti di Convegno]
Prandi, Adolfo; Franchini, Silvia; Siligardi, Cristian; P., Angeli; G., Marucci; Brasili, Livio
abstract
...
2003
- (2,2-difenil-[1,3]-diossolan-4ilmetil)-(3-fenil-propil)-ammina: nuovo agonista parziale del recettore serotoninergico 5-HT1A
[Abstract in Atti di Convegno]
Franchini, Silvia; Sorbi, Claudia; Prandi, Adolfo; P., Angeli; G., Marucci; A., Leonardi; E., Poggesi; Brasili, Livio
abstract
ABSTRACT FA-CP-027.
2003
- 1,3-Dioxolane-Based Ligands as a Novel Class of Alpha1-Adrenoceptor Antagonists
[Articolo su rivista]
Brasili, Livio; Sorbi, Claudia; Franchini, Silvia; Manicardi, M.; Angeli, P.; Marucci, G.; Leonardi, A.; Poggesi, E.
abstract
1,3-Dioxolane-based compounds (2−14) were synthesized, and the pharmacological profiles at α1-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Compound 9, with a pA2 of 7.53, 7.36, and 8.65 at α1A, α1B, and α1D, respectively, is the most potent antagonist of the series, while compound 10 with a pA2 of 8.37 at α1D subtype and selectivity ratios of 162 (α1D/α1A) and 324 (α1D/α1B) is the most selective. Binding assays in CHO cell membranes expressing human cloned α1-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of α1-adrenoceptor antagonists.
2003
- Imidazoline binding sites (IBS) profile modulation: Key role of the bridge in determining I1-IBS or I2-IBS selectivity within a series of 2-phenoxymethylimidazoline analogues
[Articolo su rivista]
F., Gentili; P., Bousquet; Brasili, Livio; M., Dontenwill; J., Feldman; F., Ghelfi; M., Giannella; A., Piergentili; W., Quaglia; M., Pigini
abstract
The α- and β-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I1- and I2-IBS selectivity. The α-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(−)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the β-methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479) proved to be considerably more potent and selective with respect to I2-IBS subtypes.
2002
- Alpha2-Adrenoceptors Profile Modulation anf High Antinociceptove Activity of (S)-)2-[1-(Biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole
[Articolo su rivista]
Gentili, F.; Bousquet, P.; Brasili, Livio; Caretto, M.; Carrieri, A.; Dontenwill, M.; Giannella, M.; Marucci, G.; Perfumi, M.; Piergentili, A.; Quaglia, W.; Rascente, C.; Pigini, M.
abstract
A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating α2-adrenoreceptors selectivity versus both α1-adrenoreceptors and I2 imidazoline binding sites. The most potent α2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the α2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15).30 (S)-(−)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with α2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with α2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective α2-antagonist RX821002.
2002
- Derivati 1,3-Diossanici come Antagonisti Muscarinici
[Abstract in Atti di Convegno]
Franchini, Silvia; Sorbi, Claudia; P., Angeli; M., Buccioni; G., Marucci; U., Gulini; Brasili, Livio
abstract
...
2002
- Nuova Serie di Ligandi Sigma a Struttura Piperazinica e Piperidinica
[Abstract in Atti di Convegno]
Costantino, Luca; Sorbi, Claudia; Franchini, Silvia; O., Prezzavento; G., Ronsisvalle; Brasili, Livio
abstract
...
2002
- Structure-Activity Relationships at alpha1-Adrenoceptor Subtypes within a New Series of 1,3-Dioxolane Derivatives
[Abstract in Atti di Convegno]
Brasili, Livio; Sorbi, Claudia; Franchini, Silvia; P., Angeli; M., Buccioni; G., Marucci
abstract
N/A
2001
- Synthesis, absolute configuration and antimuscarinic activity of the enantiomers of [1-(2,2-diphenyl-[1,3]dioxolan-4-yl)-ethyl]dimethyl-amine
[Articolo su rivista]
U., Gulini; P., Angeli; G., Marucci; M., Buccioni; D., Giardina; Antolini, Luciano; Franchini, Silvia; Sorbi, Claudia; Brasili, Livio
abstract
Methylation of the carbon atom C1 of compound 1, a potent and not selective muscarinic antagonist, was carried out. The resulting diastereomers were separated and the corresponding racemate further resolved to give four enantiomers, which were tested both as hydrogen oxalate and methiodide salts. The pharmacological results obtained at M-1, M-2 and M-3 muscarinic receptor subtypes, show that methylation at C1, depending on the stereochemistry, increases antagonist potency, having thus the same effect of nitrogen quaternization. These results may well lead to the development of new potent antimuscarinic drugs lacking a cationic head. (C) 2001 Elsevier Science Ltd. All rights reserved.
2000
- Coupling of I-1 imidazoline receptors to the cAMP pathway: Studies with a highly selective ligand, benazoline
[Articolo su rivista]
H., Greney; P., Ronde; C., Magnier; F., Maranca; C., Rascente; W., Quaglia; M., Giannella; M., Pigini; Brasili, Livio; C., Lugnier; P., Bousquet; M., Dontenwill
abstract
Clonidine and benazoline are two structurally related imidazolines. Whereas clonidine binds both to alpha(2)-adrenoceptors (alpha(2)R) and to I-1 imidazoline receptors (I1R), benazoline showed a high selectivity for imidazoline receptors. Although the alpha(2)R are negatively coupled to adenylate cyclase, no effect on cAMP level by activation of I1R has been reported so far. We therefore aimed to compare the effects of clonidine and benazoline on forskolin-stimulated cAMP levels in cell lines expressing either I1R only (PC12 cells), alpha(2)R only (HT29 cells), or I1R and alpha(2)R together (NG10815 cells). Clonidine proved able to decrease the forskolin-stimulated cAMP level in the cells expressing alpha(2)R and this effect could be blocked by rauwolscine. In contrast, in cells lacking these adrenoceptors, clonidine had no effect. On the other hand, benazoline and other I-1 receptor-selective imidazolines decreased forskolin-stimulated cAMP level in the cells expressing I1R, in a rauwolscine- and pertussis toxin-insensitive manner. These effects were antagonized by clonidine. According to these results, we demonstrated that 1) alpha(2)R and I1R are definitely different entities because they are expressed independently in different cell lines; 2) alpha(2)R and I1R are both implicated in the cAMP pathway in cells (one is sensitive to pertussis toxin and the other is not); and 3) I1R might be coupled to more then one transduction pathway. These new data will be essential to further understand the physiological implications of the I1R and the functional interactions between I-1 receptors and alpha(2)-adrenoceptors.
2000
- Enigmatic Receptors
[Relazione in Atti di Convegno]
Brasili, Livio
abstract
The identification of new binding sites raises the problem of defining their role, if any. At times they are shown to be pharmacological receptors, in a strict sense, as they fulfill certain requirements, and a precise physiological role and function, and an endogenous ligand (neurotransmitter) are discovered. At other times, however, neither a clear physiological role nor an endogenous ligand are found, but the term “receptor” is still used, although it may not be a proper one in the conventional pharmacological sense. Furthermore, no clear intracellular signalling transduction pathway is defined and, as a consequence, it is not possible to determine whether drugs binding to these receptors act as agonists or antagonists. What their structure and biological function are and how they mediate the pharmacological effects of ligands may remain for a long time an enigma. The matter, in any case, is of great interest to researchers of different areas, especially to medicinal chemists who foresee novel potential targets for therapeutic interventions. In this meeting one section is dedicated to two examples of this kind of receptors: imidazoline (I) and sigma (σ) receptors.
2000
- Structure-activity relationship at alpha-adrenergic receptors within a series of imidazoline analogues of cirazoline
[Articolo su rivista]
M., Pigini; W., Quaglia; F., Gentili; G., Marucci; F., Cantalamessa; Franchini, Silvia; Sorbi, Claudia; Brasili, Livio
abstract
Several analogues of cirazoline (2), a selective alpha(1)-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the alpha(1)-adrenoreceptor all the compounds displayed a significant agonist activity, at the alpha(2)-adrenoreceptor they showed either agonist or antagonist activity depending on the nature of the phenyl substituent. The qualitative structure-activity relationship led us to the conclusion that the oxygen atom in the side-chain is essential for alpha(1)-agonist activity, while the cyclopropyl ring is not, and may be replaced by several groups. Of the groups studied, isopropoxy appears to be the best. Instead, the same substitution (i.e., isopropoxy for the cyclopropyl ring) at alpha(2)-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for alpha(1)-selectivity. Compound 20 is the most potent alpha(1)-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat. (C) 2000 Elsevier Science Ltd. All rights reserved.
1999
- 1,3-dioxolane-based ligands in the search for alpha1-adrenergic antagonists.
[Abstract in Atti di Convegno]
Sorbi, Claudia; Franchini, Silvia; Gallesi, Rossella; Angeli, P; Marucci, G; Brasili, Livio
abstract
...
1999
- 2-(2-phenylcyclopropyl) imidazolines: Reversed enantioselective interaction at I-1 and I-2 imidazoline receptors
[Articolo su rivista]
W., Quaglia; P., Bousquet; M., Pigini; A., Carotti; A., Carrieri; M., Dontenwill; F., Gentili; M., Giannella; F., Maranca; A., Piergentili; Brasili, Livio
abstract
2-(2-Phenylcyclopropyl)imidazoline have been synthetized, the enantiomer separated and tested for their I1 and I2 receptor affinities. It was shown that the two receptor subtypes show reversed stereoselectivity.
1999
- An unexpected central hypertensive effect of the new imidazoline compound benazoline
[Articolo su rivista]
V., Bruban; J., Feldman; M., Dontenwill; H., Greney; Brasili, Livio; M., Giannella; M., Pigini; P., Bousquet
abstract
Not available
1999
- Binding of tracizolines to the imidazoline receptor - Role of lipophilicity in quantitative structure-activity relationship models
[Articolo su rivista]
M., Pigini; P., Bousquet; Brasili, Livio; A., Carrieri; M., Dontenwill; F., Gentili; M., Giannella; F., Leonetti; A., Piergentili; W., Quaglia; A., Carotti
abstract
not available
1999
- Effect of aromatic substitution on antimuscarinic activity of 2-phenyl-2-cyclohexyl-4-[(dimethylamino)methyl]-1,3-dioxolanes
[Articolo su rivista]
P., Angeli; Brasili, Livio; Franchini, Silvia; D., Giardina; U., Gulini; G., Marucci
abstract
A series of 2-substituted 1,3-dioxolane ligands were synthesized and tested as muscarinic antagonists. The compounds display moderate to high affinity for the three receptor subtypes M-1-M-3, With some of them showing a modest selectivity for the M-1 subtype.
1999
- Synthesis and Anti-HIV Activity of 1,3-Dithiolane Nucleosides
[Articolo su rivista]
N., Nguyn Ba; W. L., Brown; L., Chan; N., Lee; Brasili, Livio; D., Lafleur; B., Zacharie
abstract
Not available
1998
- 1 '-Benzyl-3,4-dihydrospiro[2H-1-benzothiopyran-2,4 '-piperidine] (Spipethiane), a potent and highly selective sigma(1) ligand
[Articolo su rivista]
W., Quaglia; M., Giannella; A., Piergentili; M., Pigini; Brasili, Livio; R., Di Toro; L., Rossetti; S., Spampinato; C., Melchiorre
abstract
Not available
1998
- Ligand binding to I-2 imidazoline receptor: The role of lipophilicity in quantitative structure-activity relationship models
[Articolo su rivista]
M., Pigini; P., Bousquet; Brasili, Livio; A., Carrieri; R., Cavagna; M., Dontenwill; F., Gentili; M., Giannella; F., Leonetti; A., Piergentili; W., Quaglia; A., Carotti
abstract
A series of 2-trans-styryl-imidazoline (tracizoline) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I-2) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I-2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I-2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high It receptor affinity. (C) 1998 Elsevier Science Ltd. All rights reserved.
1998
- Sintesi e attivita' farmacologica di alcuni N-(1,3-diossolan-2-il-metil)-lattami
[Abstract in Atti di Convegno]
Marucci, G; Malmusi, L; Franchini, Silvia; Angeli, P; Gulini, U; Brasili, Livio
abstract
...
1998
- Synthesis and Antimuscarinic Activity of Some Ether- and Thioether-Bearing 1,3-dioxolanes and Related Sulfoxides and Sulfones
[Articolo su rivista]
L., Malmusi; Franchini, Silvia; Mucci, Adele; Schenetti, Luisa; U., Gulini; G., Marucci; Brasili, Livio
abstract
A series of 1,3-dioxolane-based ligands, bearing ether, thioether and related sulfoxide and sulfone functionalities, were synthsised and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M1-M3, with some of them showing a significant selectivity for the M1-M3 over the M2 subtype.
1998
- Synthesis and antimuscarinic activity of some N-(4-dimethylaminomethyl-2-phenyl-1,3)dioxolan-2-ylmethyl)lactam methiodides
[Articolo su rivista]
L., Malmusi; Franchini, Silvia; Mucci, Adele; P., Angeli; U., Gulini; G., Marucci; Brasili, Livio
abstract
A series of 1,3-dioxolane-based ligands, having a lactam function were synthesized and tested as potential muscarinic antagonists. The compounds display moderate affinity for the three receptor subtypes M1-M3, with significant selectivity for the M1-M3 over the M2 subtype.
1997
- 2-D and 3-D modeling of imidazoline receptor ligands: Insights into pharmacophore
[Articolo su rivista]
A., Carrieri; Brasili, Livio; F., Leonetti; M., Pigini; M., Giannella; P., Bousquet; A., Carotti
abstract
A 3-D quantitative structure-activity relationship (3-D QSAR) study was carried out using comparative molecular field analysis (CoMFA) on both imidazoline (I2R) and alpha(2) receptor binding affinities of a large series of 2-substituted imidazolines. Significant cross-validated correlations, having promising predictive ability, were obtained along with 3-D pharmacophore models that defined the spatial regions where steric and electrostatic interactions may modulate the in vitro binding affinities and indicated possible physicochemical and structural requirements for I-2/alpha(2) receptor selectivity.
1997
- Imidazoline receptors: Qualitative structure-activity relationships and discovery of tracizoline and benazoline. Two ligands with high affinity and unprecedented selectivity
[Articolo su rivista]
M., Pigini; P., Bousquet; A., Carotti; M., Dontenwill; M., Giannella; R., Moriconi; A., Piergentili; W., Quaglia; Sk, Tayebati; Brasili, Livio
abstract
The observation that all the attempts to characterize imidazoline (I) receptors have been carried out with non-selective or poorly selective ligands prompted us to undertake research aimed at developing selective ligand(s). In previous work using, as a starting point, cirazoline 1, a potent alpha(1)-adrenergic receptor agonist that also binds to I receptors, we showed that removal of the cyclopropyl ring (2) retains high affinity for I-2 receptors while reducing alpha(1)-adrenergic agonist activity. However, it was felt that this residual, albeit modest, alpha(1)-adrenergic agonist activity might diminish the usefulness of compound 2, and we now report on our continuing efforts in this field. Starting from compound 2, we first eliminated the alpha(1)-agonist component by isosteric replacement and then, by means of conformational restrictions on compound 7, succeeded in discovering tracizoline (9) and benazoline (12). These two new ligands with high affinity (pK(i) value 8.74 and 9.07, respectively) and unprecedented selectivity with respect to both alpha(2)-(I-2/alpha(2) 7,762 and 18,621) and alpha(1)-(I-2/alpha(1) 2,344 and 2,691) adrenergic receptors, are valuable tools in the study of I receptor structure and function. In addition, the large number of derivatives studied has allowed us to establish congruent qualitative structure-activity relationships and identify some structural elements governing affinity and selectivity.
1997
- Synthesis and structure-activity relationship studies in a series of 2-substituted 1,3-dioxolanes modified at the cationic head
[Articolo su rivista]
P., Angeli; Brasili, Livio; M. L., Cingolani; G., Marucci; A., Piergentili; M., Pigini; W., Quaglia
abstract
To develop ligands that may be useful in exploring muscarinic receptor heterogeneity, we synthesized a series of analogues of 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine oxalate and methiodide bearing a modified cationic head. These compounds, when tested on tissues containing the three subtypes M-1, M-2, and M-3, behaved as muscarinic antagonists whose results showed that different substituents on the quaternary and tertiary nitrogen affect affinity and selectivity in different ways. In particular, comparison of the affinities of these ligands with those of the reference compounds points out that compounds bearing an ethyl substituent improve the affinity of the molecule at the three subtypes, while compounds bearing a phenethyl substituent are more selective for the M-3 sites.
1996
- Synthesis, NMR spectroscopy study, and antimuscarinic activity of a series of 2-(acyloxymethyl)-1,3-dioxolanes
[Articolo su rivista]
L., Malmusi; Mucci, Adele; Schenetti, Luisa; U., Gulini; G., Marucci; Brasili, Livio
abstract
A series of 1,3-dioxolane-based ligands, bearing hydroxymethyl or ester functionalities, was synthesized and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M(1)-M(3), with some of them showing a significant selectivity for the M(3) subtype. The configurational and conformational properties were studied using NOE experiments and vicinal coupling constants. The LH and C-13 NMR chemical shifts show stereochemically dependent trends. Quantitative analysis of conformer populations showed that the exocyclic CH2N+(CH3)(3) group is prevalently in a pseudo-axial orientation in the cis isomers and in a pseudo-equatorial orientation in the trans isomers. Copyright
1995
- CONFORMATIONAL AND CONFIGURATIONAL STUDY OF 1,3-DIOXOLANES BY PROTON AND CARBON NMR-SPECTROSCOPY
[Articolo su rivista]
Mucci, Adele; Schenetti, Luisa; Brasili, Livio; Malmusi, L.
abstract
The configurational and conformational properties of six 4-trimethylammoniummethyl 2,2-disubstituted 1,3-dioxolanes were studied using NOE experiments and vicinal coupling constants. Selective 1D NOE experiments proved to be effective tools in the configurational assignment of C-2 relative to C-4, The preferred conformation of the dioxolane ring and the exocyclic group at C-4 was obtained by employing vicinal coupling constants and NOE results. The H-1 and C-13 NMR chemical shifts show stereochemically dependent trends, Quantitative analysis of conformer populations was performed using Haasnoot et al's equation. The -N+(CH3)(3) group was found to be synclinal with respect to the heterocyclic 0-3 atom and points outside the ring, When a phenyl group is present at C-2, the 4-CH2N+ - group in a trans relationship to the 2-phenyl ring was found to occur prevalently in a pseudo-axial orientation, whereas it was established to be prevalently pseudo-equatorial when cis with respect to the phenyl ring.
1995
- Separation of alpha-adrenergic and imidazoline/guanidinium receptive sites 4IGRS) activity in a series of imidazoline analogues of cirazoline
[Articolo su rivista]
Brasili, Livio; M., Pigini; G., Marucci; W., Quaglia; L., Malmusi; Sm, Lanier; B., Lanier
abstract
To characterize the structure-activity relationship between alpha(1)-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha(1)-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pK(i) 7.9) than for alpha(1)-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha(1)-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pK(i) 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha(1)-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pK(i) 8.08) and high selectivity (228 and 138) with respect to the alpha(2B), and alpha 2(C)-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.
1994
- SYNTHESIS AND MUSCARINIC RECEPTORS AFFINITY OF A SERIES OF ANTAGONIST BIVALENT LIGANDS
[Articolo su rivista]
Piergentili, A; Quaglia, W; Tayebati, Sk; Paparelli, F; Malmusi, L; Brasili, Livio
abstract
A series of bivalent ligands (2-8) derived from 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-d amine methiodide 1 has been synthesized and tested to evaluate affinity and selectivity for M(1), M(2) and M(3) muscarinic receptor subtypes. In order to study the contribution of the spacer and of a second cationic head to the binding process, unsymmetrical ligands (9,10) have also been prepared. The results, expressed in terms of pA(2) values, show that, although the spacer negatively affects the interaction of the bivalent ligands with the three receptor subtypes, affinity and selectivity are modulated by its length; this indicates that the pharmacophore binding sites are organized differently with respect to their mutual proximity and orientation, in each receptor subtype.
1993
- A Novel Class of 1,3-Oxathiolane Nuclosides Analogues Having Potent Anti-HIV Activity.
[Articolo su rivista]
Belleau, B.; Brasili, Livio; Chan, L.; DI MARCO, M.; Zacharie, B.; NGUYEN BA, N.; Jenkinson, H. J.; Coates, J. A. V.; Cameron, J. M.
abstract
A novel class of 1,3-oxathiolane nucleoside analogues have been developed and evaluated as anti-HIV activity in the MT-4 cell line. BHC-371, the adenine derivatives has been found to exhibit significant anti-HIV activity.
1993
- Determination of Muscarinic Agonist Potencies at M1 and M2 Receptors in Pithed Rat
[Articolo su rivista]
Angeli, P.; Brasili, Livio; Gulini, U.; Cantalamessa, F.
abstract
The agonist potency of 2-cia-methyl-5-dimethylaminomethyl-1,3-oxathiolane-3-traqns-oxide methiodide and its two enantiomers were detemined in vivo at muscarinic M1 and M2 receptors. The results indicate a selectivity of 5-8 fold for M1 receptors, confirming the M1 profile of the oxathiolane nucleus.
1992
- Effect of Deoxamuscarine Etherification on M2 and M3 Muscarinic Affinity and Efficacy
[Articolo su rivista]
Brasili, Livio; Giannella, M.; Piergentili, A.; Tayebati, S. K.
abstract
A series of ether derivatives of deoxamuscarine were synthesized and tested for muscarinic activity on guinea-pig heart, ileum, and bladder. The results show that: a) The introduction ofthe benzyl group generates an agonist which is 5-fold more potent and 10-fold more selective than deoxamuscarine on ileum. This selectivity is ascribed to an increase of efficacy. b) Affinity and efficacy are differently affected by the substituents studied. c) The so-called muscarinic subsite interacting with the hydroxy group of muscarine-like compounds may acconìmodate bulky substituents, and on the basis of this new functionalized congeners may be designed with a view to achieving more potent and more selective muscarinic ligands.
1992
- Pharmacological Characterization of Chiral Muscarinic Antagonists cis-2-Phenyl-2-cyclohexyl-r-5-[(dimethylamino)-methyl]1,3-oxathiolane-3-oxide Methiodide
[Articolo su rivista]
Angeli, P.; Balduini, W.; Brasili, Livio; Cantalamessa, F.; Cattabeni, F.; Marucci, G.
abstract
. Cis-2-phenyl-2-cyclohexyl-r-5 [(dimethylamino)-methyl]-1,3-oxathiolane cis [(±)1] and trans [(±)2] 3-oxide methiodides together with the enantiomers (+)2 and (-)2 where evaluated for their antimuscarinic activity in functional (in vivo and in vitro) and in binding studies. The results indicate that in all the receptor subtypes the trans isomer (±)2 is more active than the cis one (±)1. Of the two enantiomers, (+)2 displays the highest affinity while the values of eudismic ratios, although large, are similar for all the subtypes. Furthermore, the tested oxathiolanes show a small degree of selectivity in binding studies while in functional studies selectivity is absent.
1992
- Synthesis, Pharmacological Evaluation and Selectivity Profile of Isomeric 2-Phenyl-2-cyclohexyl-4-[(dimethylamino)methyl]-1,3-dithiolane Methiodide as Potent Antimuscarinic Agents
[Articolo su rivista]
Angeli, P.; Brasili, Livio; Gulini, U.; Marucci, G.; Paparelli, F.
abstract
The synthesis and antimuscarinic activity on M1, M 2 and M3 tissues of cis- and trans-2-phenyl-2-cyclohexyl-4-[(dimethylamino)-methyl]-1,3-dithiolane methiodides (1 and 2)are described. Our results show that compound 1 is a potent and Mr1 selective muscarinic antagonist.
1991
- Pharmacological Characterizazion of Muscarinic Receptor Subtypes in Rabbit Isolated Tissue Preparation
[Articolo su rivista]
Angeli, P.; Brasili, Livio; Cingolani, M. L.; Marucci, G.; Pigini, M.; Tonnini, C.
abstract
1. The affinity of some muscarinic antagonists for muscarinic receptors was determined in functional isolated tissue studies in order to compare the muscarinic receptor subtypes in the rabbit.2. Our attention was specially focused on the question of whether the muscarinic receptors mediating vasodilatation in the aorta resemble or not the ones present on the jejunum of the gastrointestinal tract.3. Isolated aorta, jejunum, stimulated left atrium and vas deferens preparations of rabbit were investigated with the following muscarinic antagonists: atropine, pirenzepine, methoctramine (N,N'-bis[6-(2-methoxybenzyl)amino hexyl]-1, 8-octane-diamine tetrahydrochloride) and 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide).4 .The results demonstrate that the receptors on aorta are unlike those on the other rabbit tissues: pirenzepine pA2 was 6.4 on aorta but 8.1 on vas deferens; methoctramine pA2 was 5.9 on aorta but 7.1 on heart; 4-DAMP pA2 was 8.7 on aorta and 8.0 on jejunum. This raises the question: what subtype might be involved?
1990
- Determination of Muscarinic Agonist Potencies at M1 and M2 Muscarinic Receptors in a Modified Pithed Rat
[Articolo su rivista]
Angeli, P.; Brasili, Livio; Cantalamessa, F.; Marucci, G.; Wess, J.
abstract
The agonistic potencies of (±)muscarine, (±)cis-2-methyl-5-[(dimethylamino)methyl]-1,3 -oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M1 and M2 receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M2 receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, "true" M1 and M2 potencies were determined after selective blockade of M1 and M2 receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M1 and M2 receptors: (+)cis-oxathiolane > (±)cis-oxathiolane > (±)muscarine > (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-lold) than its corresponding (-) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While (±)muscarine showed similar potencies at M1 and M2 receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3 - 7 fold) for M1 receptors indicating the potential usefulness of these compounds in the development of selective M1 receptor agonists.
1989
- Structure-Activity Relationships in Prazosin-Related Compounds. Effect of Replacing a Piuperazine Ring with an Alkanediamine Moiety on alpa1-Adrenoreceptor Blocking Activity.
[Articolo su rivista]
Giardin, D.; Brasili, Livio; Gregori, M.; Massi, M.; Picchio, M. T.; Quaglia, W.; Melchiorre, C.
abstract
Several prazosin-related compounds were synthesized in which the piperazine ring of prazosin (1) was replaced byan alkanediamine chain and were evaluated for their blocking activity on al- and a2-adrenoreceptors in isolatedrat vas deferens. All the compounds investigated proved highly selective toward the al-adrenoreceptor owing toa very low affinity for a2-adrenoreceptors. Furthermore, compounds 2,9, and 13 were also investigated in vivo todetermine their hypotensive effect on anesthetized rats, which were compared with that of prazosin (1). It was confirmedthat the piperazine moiety of 1 is not essential for potency. However, optimum activity depends on two parameters:carbon-chain length of the alkanediamine moiety and N-methylation of both the amide and the 2-amino functions.In the desmethyl series, optimum activity was associated with the lower homologues (2-4) bearing a chain of twoto four methylenes whereas in the N,N'-dimethyl series peak potency was observed with a six-carbon chain as in13. Compound 13 proved the most active of the series and was more potent than prazosin (1) in both in vivo andin vitro assays. It is hypothesized that the a,-adrenoreceptor incorporates a lipophilic area that is located betweenthe binding sites for the quinazoline and the furoyl moieties and is able to accommodate a polymethylene chain.
1989
- Structure_Activity Relationships among Methoctramine-Related Polymethylene Tetramine. Chain Length and Substituent Effects on M2 Muscarinic Receptor Blocking Activity.
[Articolo su rivista]
Melchiorre, C.; Quaglia, W.; Picchio, M. T.; Giardin, D.; Brasili, Livio; Angeli, P.
abstract
Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blockingactivity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency dependson the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chainlength separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the innernitrogens and six methylenes between the inner and outer nitrogens. With regard to the substitueats, replacementof the benzylic moiety of 1 by a 2-fury1 or a 5-methyl-2-fury1 nucleus resulted in enhanced potency toward cardiacM-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selectivethan 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens,giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resultedin an increase in activity in both atria and ileum.
1988
- Alpha-Adrenoceptor occupancy by N,N-dimethyl-2-bromo-2-phenethylamine hydrobromide (DMPEA) in rat vas deferens
[Articolo su rivista]
Carlo, Melchiorre; Anna, Cassinelli; Brasili, Livio; Dario, Giardinà; Ugo, Gulini; Wilma, Quaglia
abstract
The effects of N,N-dimethyl-2-bromo-2-phenethylamine hydrobromide (DMPEA) on alpha1- and alpha2-adrenoceptors were examined in the isolated rat vas deferens. The active species of DMPEA was the corresponding ethyleniminium ion, which forms in the biophase, since pretreatment of tissues with sodium thiosulphate completely prevented the DMPEA-induced inhibition at alpha1- and alpha2-adrenoceptors. DMPEA was approximately 42-fold more potent in inhibiting alpha2-adrenoceptors than it was in inhibiting alpha1-adrenoceptors. The antagonism of both receptor types was reversible since washing of the tissues after incubation with DMPEA brought the agonist dose-response curve back to the control value. At alpha1-adrenoceptors, DMPEA displaced the noradrenaline dose-response curve to the right and concomitantly depressed the maximum response, effects which are consistent with a non-competitive mechanism of action. At alpha2-adrenoceptors, DMPEA caused a parallel shift of the clonidine or noradrenaline dose-response curve to the right in field-stimulated prostatic portions of the rat vas deferens. The antagonism appeared to be competitive at low concentrations, whereas the shift of the clonidine dose-response curve at higher concentrations became overproportional to the DMPEA concentration. A combination of DMPEA with idazoxan produced a less-than-additive shift of the dose-response curve for clonidine, indicating that these antagonists do not bind to the same site.
1988
- Chiral muscarinic agonists possessing a l,3-oxathiolane nucleus: enantio- and tissue-selectivity on isolated preparations of guinea-pig ileum and atria and of rat urinary bladder
[Articolo su rivista]
P., Angeli; Brasili, Livio; M., Giannella; F., Gualtieri; M. T., Picchio; E., Teodori
abstract
Racemate and corresponding enantiomers of muscarinic agonists carrying a 1,3-oxathiolane nucleus were studied on isolated preparations of guinea-pig ileum and atria and of rat urinary bladder. The efficacy of these agonists were determined according to the method of Furchgott and Bursztyn (1967) and enantio-selectivity and tissue-selectivity were investigated. The enantio-selectivities of the most potent compounds studied (expressed as the ratio of potencies or affinities of the enantiomers) vary significantly from tissue to tissue, supporting the view that M2 receptors are not homogeneous. In particular, the data all indicate that the ileal receptors are different to the atrial and bladder ones.
1988
- ENANTIO- AND TISSUE-SETECTIVITY OF CHIRAL MUSCARINIC AGONISTS CARRYING A 1.3-OXATHIOLANE NUCLEUS
[Relazione in Atti di Convegno]
F., Angeli; Brasili, Livio; F., Gualtier; E., Teodori
abstract
ln order to investigate tissue and enantioserectivity of 1,3-oxathiolane muscarinic agonists we have estimated potency, affinity and relative efficacy according to Furchgott and Bursztyn on isolated preparations of guinea pig ileum, atria and rat urinary bladder.
1988
- ENANTIOSELECTIVITY OF CHTRAL CHOLINERGI AGONISTS AND ANTAGONISTS CARRYING A 1,3-OXATHTOLANE NUCLEUSAGONISTS AND ANTAGONTSTS
[Relazione in Atti di Convegno]
F., Gualtieri; P., Angeli; Brasili, Livio; M., Giannella; M. T., Picchio; M. N., Romanelli; E., Teodori
abstract
The results of a study concerning the enantioselectivity of chiral colinergic agonists and antagonists carrying a 1,3-oxathiolane nucleus are reported. Enantiosetrectivity is usually high for agonists and low for antagonists. It can change from tissue to tissue supports the existence of differences amoung muscarinic M2 receptorsComparison of the stereoisomeries of agonist and antagonist interactions suggests that both kinds of ligand interact with a common binding site on the receptor molecu1e.
1988
- Enantioselectivity of Muscarinic Antagonists. 2,2-Dicyclohexyl-5-((dimethylamino)methyl)-1,3-oxathiolane Methiodide and Related 3-oxide.
[Articolo su rivista]
Romanelli, M. N.; Teodori, E.; Gualtieri, F.; Brasili, Livio
abstract
The enantiomers of three chiral muscarinic antagonists carrying a 1,3-oxathiolane nucleus were prepared and theirabsolute configuration established. The enantioselectivity and tissue selectivity of such compounds were studiedon rat bladder and guinea pig ileum and heart. The results show that introduction of a sulfoxide function bringsabout a small but definite enantioselectivity in the 1,3-oxathiolane compound (2), which in itself does not showenantioselectivity among the tissues studied. The results obtained point to differences among cardiac and ilealmuscarinic receptors. Comparison of the absolute configuration related shows that the most potent isomersof both series share the same absolute stereochemistry.
1988
- Enantioselectivity of Muscarinic Antagonists. Isomeric 2-Cyclohexyl-2-phenyl-5-(dimethylamino)methyl)-1,3-oxathiolane
[Articolo su rivista]
Romanelli, M. N.; Gualtieri, F.; Valle, G.; Brasili, Livio; Angeli, P.
abstract
The four isomers of 2-cyclohexyl-2-phenyl-[5 (-d imethylamino)methyl]-l,3-oxathiolanmee thiodide were prepared.Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compoundswere tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated andexpressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a smallbut definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. Thissupports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparisonof the absolute configuration of the antagonists studied in this and in the preceding papel.2 and that of strictly relatedagonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.
1988
- POLYAMINES: A POSSIBLE “PASSE-PARTOUT” FOR RECEPTOR CHARACTERIZZATION
[Relazione in Atti di Convegno]
C., Melchiorre; P., Angeli; Brasili, Livio; D., Giardinà; U., Gulini; M., Pigini; W., Quaglia
abstract
It is evident that drug specificity can be improved by increasing the number of interactions with the complementary receptor site. Considering that a protein may bear several carboxylic groups, in principle, polycationic compounds could well represent selective ligands for receptor molecules provided the distance separating the nitrogen atoms of polyamine would be fit the distance between the carboxylic groups of the receptors.It is this rationale that served as the basis for development of polymethylene polyamines as selective inhibitors of different neurotransmitter receptors. The highlights of our findings are described.
1988
- Structure-Activity Relationships Among Benextramine Related Tetramine Disulfidxe. Chain Length Effect on alpha-adrenoreceptor Blocking Activity.
[Articolo su rivista]
Quaglia, W.; Brasili, Livio; Cristalli, G.; Giardin, D.; Picchio, M. T.; Melchiorre, C.
abstract
Several N'-substituted N~"-(dithiodi-2,l-ethanediyl)bis(l,w-alkanediamines)w ere prepared and evaluated for theirblocking activity on a-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results werecompared with those obtained for benextramine (N,N"-(dithiodi-2,l-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl] - 1 ,g-hexanediamine], 10). Bendotramine (N,"'- (dithiodi-2,1 -ethanediyl) bis [ N'- [ (2-methoxypheny1)-methyl]-1,12-dodecanediamine]1,6 ) proved to be as active as 10 on al-adrenoreceptors, showing that optimum activityis associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On theother hand, 16 had no activity up to 20 pM at a2-adrenoreceptors. The optimum activity at this receptor subtypewas associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective towarda,-adrenoreceptors whereas 16 was a selective al-antagonist. The tetraamine disulfides were shown also to be potentinhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbonchain length. However, the results on platelets did not parallel those found in the rat vas deferens, indicating thatdifferences exist between the a-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool incharacterizing a,-adrenoreceptors whereas 16 might help in investigating a,-adrenoreceptors.
1988
- Structure-Activity Relationships in 1,4-Benzodioxane Related Compounds. Investigation on the Role of the Dehydrodioxane Ring on alpha1-Adrenoreceptor Blocking Activity.
[Articolo su rivista]
Pigini, M.; Brasili, Livio; Giannella, M.; Giardin, D.; Gulini, U.; Quaglia, W.; Melchiorre, C.
abstract
Several analogues of 2 4 [ [2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-l,4-benzodiox(aWn B 4101, 1) were preparedand evaluated for their blocking activity on al- and az-adrenoreceptors in the isolated rat vas deferens. The resultswere compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contributeto the binding while it is important in stabilizing an optimal conformation for drug-receptor interaction mechanism.On the other hand, the oxygen at position 1 might interact with a receptor polar pocket of reduced size by way ofa donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity.
1988
- Synthesis and Pharmacological Evaluation of Some Analogues of the Ca-Antagonist Cinnarizine
[Articolo su rivista]
Stelano, Corsano; Giovannella, Strappaghetti; Brasili, Livio
abstract
Several compounds were prepared by coupling one of the two moieties of cinnarizine (1) with one of the two moieties of WB 4101 (2). In addition, compounds were synthesized lacking the piperazine ring. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guinea-pig. These new compounds show lower activities as Ca antagonists than Cinnarizine (1).
1987
- Fluoronorepinephrines: further pharmacological evaluation in vitro and in pithed rats
[Articolo su rivista]
Brasili, Livio; Franco, Cantalamessa; Maria T., Picchio; Wilma, Quaglia
abstract
The effect of 6F-, 5F- and 2F-norepinephrine (6F-, 5F- and 2F-NE) in rat vas deferens, guinea-pig ileum and pithed rats was compared to that of norepinephrine (NE). The rank order of potency on postsynaptic alpha1-adrenoreceptors, determined from the isometric contraction of vas deferens, was 6F-NE = 5F-NE = NE > 2F-NE. A similar pattern was found for presynaptic alpha2-adrenoreceptor activity in both noradrenergic nerve terminals of vas deferens and cholinergic nerve terminals of the ileum, determined from the inhibition of contraction elicited by electrical field stimulation. The only exception was the 5F isomer which was 7 times less active than NE to activate the alpha2-adrenoreceptors of vas deferens. Thus, ring fluorination markedly alters both alpha1- and alpha2-agonist properties of NE. Moreover, alpha1/alpha2 selectivity, at least as far as rat vas deferens is concerned, is not significantly influenced by the introduction of a fluorine atom in the NE molecule. 6F-NE was about 3-4 times more active than NE in pithed rats. In turn, NE was equiactive with 5F-NE. 2F-NE was the least active isomer, being 30- and 100-fo1d less active than NE and 6F-NE, respectively.
1987
- Resolution of the potent α1-adrenoreceptor antagonist 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian (benoxathian)
[Articolo su rivista]
A., Cassinelli; W., Quaglia; Brasili, Livio; D., Giardinà; U., Gulini; C., Melchiorre
abstract
The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian hydrochloride (1: benoxathian) were prepared from the chiral 1,4-benzoxathian-2-carboxylic acids [(+)- and (−)-3] which in turn were obtained through the resolution of the racemic acid with R- and S-α-methylbenzylamine. Their blocking activities and relative selectivities on α1- and α2-adrenoreceptors were evaluated on isolated rat vas deferens. For α1-adrenoreceptors the enantiomer (−)-1 was 10 times more potent than the enantiomer (+)-1, whereas no significant difference between the blocking activity of the enantiomers was observed for α2-adrenoreceptors. Furthermore, the enantiomer (−)-1 showed high activity and selectivity toward the α1-adrenoreceptor (pA2 = 9.36; selectivity ratio = 1230) which may have relevance in the characterization of α-adrenoreceptor subtypes.
1987
- Resolution, Absolute Configuration and Cholinergic Enantioselectivity of (-) and (+) c-2-Methyl-r-5-((Dimethylamino(methyl)-1,3-oxathiuolane-t-oxide Methiodide and Related Sulfones.
[Articolo su rivista]
Teodori, E.; Gualtieri, F.; Angeli, P.; Brasili, Livio; Giannella, M.
abstract
As a continuation of previous studies on chiral cholinergic agonists carrying a 1,3-oxathiolane nucleus, the enantiomersof c-2-methyl-r-5-[(dimethylamino)methyl]-l,3-oxathiolta-n3e-o xide methiodide ((+)- and (-)-l) and of cis-2-methyl-5-[ (dimethylamino)methyl]-1,3-oxathiolane3 ,3-dioxide ((+)- and (-)-2) were obtained and their absoluteconfigurations established by synthesis. The cholinergic potency of the four isomers was evaluated in vitro on guineapig ileum and frog rectus abdominis models, and the results show that (-)-1, which has the same absolute configurationas L-(+)-muscarine, is a selective and potent muscarinic agent. The (+)-1 enantiomer is some hundred times lesspotent than (-)-1 on the muscarinic guinea pig ileum while, on the same tissue, the corresponding sulfone derivatives((+)- and (-)-2) show no enantioselectivity.
1987
- Synthesis and alpha blocking activity of some analogues of idazoxan
[Articolo su rivista]
M., Pigini; Brasili, Livio; A., Cassinelli; D., Giardina; U., Gulini; W., Quaglia; C., Melchiorre
abstract
Several analogues of idazoxan 1 and fenmetazole 2 were prepared as potential alpha-adrenoreceptor antagonists.Their blocking activity and selectivity on al- and a,-adrenoreceptors were evaluated in isolated rat vas deferens. Althoughall the drugs displayed a significantly lower activity compared to the parent compounds 1 and 2, with 3 being the only exception,the present results might help in elucidating the role of ring oxygens of 1 in drug-receptor interaction.
1986
- HYPOTENSIVE EFFECT IN DOGS AND RATS OF INTRAVENOUS INJECTIONS OF THE 1-ADRENORECEPTOR ANTAGONIST BENOXATHIAN
[Articolo su rivista]
Maurizio, Massi; Fabrizio, Venturi; Brasili, Livio; Carlo, Melchiorre
abstract
The hypotensive effect of the alpha1-adrenoreceptor antagonist benoxathian has been evaluated in rats and dogs, in comparison to that evoked by WB 4101 and prazosin, In anaesthetized dogs, i.v. injection of benoxathian (25-100 g/kg), WB 4101 (5-25 g/kg) and prazosin (50g/kg) produced an immediate fall in diastolic blood pressure, which reached a maximum at about 30 sec after drug administration, whereas the hypotensive effect of prazosin persisted up to 3 hr following injection, the effect of both benoxathian and WB 4101 completely disappeared after 30-60 min. The hypotenslve effect of benoxathlan was dose-dependent. Pressor responses to i.v. noradrenaline (5g/kg), adrenaline (5g/kg) and phenylephrine (20 g/kg) were markedly inhibited (60-75%) by benoxathlan (100g/kg) whilst the pressor response to angiotensin II (0,05 g/kg) was not reduced, but indeed slightly increased. The hypotensive effect of benoxathian (100 g/kg) was abolished following pre-treatment with prazosin (50 g/kg) or hexamethonium (1000 g/kg). In anaesthetized rats similar results were obtained although recovery in blood pressure from the initial drop after i.v, injection of the drugs was slower than in dogs. Benoxathian was slightly more toxic than WB 4101 in rats. In conclusion, present findings show that benoxathlan causes a profound hypotensive effect in dogs and in rats through postsynaptic -adrenoreceptor blockade; however 1ts effect, as well as that of WB 4101, is shorter lasting than that of prazosln.
1986
- Resolution, Absolute Configuration and Cholinergic Enantioselectivity of (+) and (-) cis-2-Methyl-5-dimethylaminomethyl-1,3-oxathiolane Methiodide.
[Articolo su rivista]
Teodori, E.; Gualtieri, F.; Angeli, P.; Brasili, Livio; Giannella, M. PIGINI M.
abstract
The potent cholinergic agonist (i)-cis-2-methyl-5-[(dimethylamino)methyl]-1,3-oxathiolamnee thiodide [ (+l] wasresolved into enantiomeric forms. Their absolute configurations were established by a synthetic pathway that alsoallowed the synthesis of the corresponding diastereomeric (+)- and (-)-trans-2-methyl-5-[(dimethylamino)-methyl]-l,3-oxathiolane methiodide [(+)- and (-)-lo]. Compound (+)-lw, hich is the most potent of the four isomers,showed the same absolute configuration as L-(+)-muscarine and (+)-cis-dioxolane. The four isomers were testedon guinea pig ileum and frog rectus abdominis, and their muscarinic and nicotinic potency (EPMR) and selectivitywere determined. The relationships between stereoisomerism and potency are discussed.
1986
- SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF CYCLIC AND OPENED THIOANALOGUES OF PIPEROXAN
[Articolo su rivista]
G., Strappaghetti; Brasili, Livio
abstract
Three piperoxan analogues, derived from the opening of the benzodioxane ring and/or replacement of the oxygen atom with the less polar sulfur, were synthesized. The decrease of the -blocking activity found for these compounds showed that the binding site of benzodioxane-like compounds does not accept the substitution with less polar groups.
1986
- THIOL GROUP MAY BE INVOLVED IN THE IRREVERSIBLE BLOCKADE OF PRESYNAPTIC 2-ADRENORECEPTORS BY PYREXTRAMINE AND BENEXTRAMINE IN THE ISOLATED GUINEA PIG ILEUM
[Articolo su rivista]
Brasili, Livio; Anna, Cassinelli; Piero, Angeli; Carlo, Melchiorre
abstract
This study, conducted on isolated guìnea pig ileum, was designed to establish the mechanism of presynaptic 2-adrenoreceptor blockade by the tetramine disulfides, benextramine and pyrextramine. At 1 M these drugs irreversibly blocked norepìnephrine (NE)-induced inhibition of the twitch response to electrical stimulation. This may be the result of covalent bond formation between the disulfide bridge of the inhibitor and a thiol function at the receptor level through an interchange reaction since the benextramine carbon analogue did not affect NE response under the same conditions. Furthermore, NE (10 uM) failed to protect presynaptic 2-adrenoreceptors from pyrextramine blockade whereas idazoxan (0.1 M) completely abolished the irreversible antagonism of pyrextramine (l uM). Thjs finding suggests that the tetramine disulfide binding site may coincide with that of idazoxan and is different from the NE binding site.
1985
- Affinity and efficacy correlate with chemical structuremore than potency does in a series of pentatomic cyclicmuscarinic agonists
[Articolo su rivista]
P., Angeli; Brasili, Livio; M., Giannella; F., Gualtierix; M., Pigini
abstract
1 The efficacy and affinity of nine pentatomic cyclic muscarinic agonists were determined on theguinea-pig ileum, according to the method of Furchgott & Bursztyn {1967). 2 Tbe efficacy and affinity of these agonists are affected differently by structural modifications.3 Our results suggest that a strong dipole oriented in the same direction as that of the hydroxy groupof muscarine, or the presence of a polarizable atom in the same position, are important for efficacy
1985
- Pentatomic cyclic compounds as probes forthe cholinergic receptor
[Relazione in Atti di Convegno]
Fulvio, Gualtieri; Piero, Angeli; Brasili, Livio; Mariogiannella, ; Maria, Pigini
abstract
In this paper we describe the results obtained in the last few years studyingstructure-activity relationships in pentatomic cyclic compounds related to muscarine, with the aim of understanding the molecular requirements of the cholinergic receptor recognition site with particular reference to the muscarinic subtype.
1985
- Structure-Activity Relationships Among Benextramine-Related Tetramine Disulfide at Peripheral Alpha-Adrenoreceptors.
[Articolo su rivista]
Angeli, P.; Brasili, Livio; Brancia, E.; Giardin, D.; Quaglia, W.; Melchiorre, C.
abstract
Several N,”’-(dithiodi-2,1-ethanediyl) bis~N’-(arylmethyl)-l,6-hexanediaminewse]r e prepared and evaluated fortheir blocking activity on postsynaptic al-adrenoreceptors in the isolated rat vas deferens. The results were comparedwith those obtained for benextramine (I). N~’~(Dithiodi-2,1-ethanediyl)bis[N’-(pyrrol-2-ylmethyl)-1,6-hexanediamine](pyrextramine, 29) was the most potent among the tetraamine disulfides investigated. Thus, it was selected forfurther pharmacological evaluation to assess its receptor specificity. At a concentration of 10 WM it did not affectthe responses elicited by 5-hydroxytryptamine and histamine in guinea pig ileum and by isoproterenol in guineapig atria and tracheal chain. Furthermore, it was more specific than benextramine (1) toward the muscarinic receptor,being significantly less potent in inhibiting the carbachol-induced response in rat jejunum. These results show thatpyrextramine (29) is an irreversible a-blocking agent that is more potent and specific than benextramine (I). Inconclusion, 29 may be a useful tool in the elucidation and characterization of the peripheral al-adrenoreceptor.
1985
- Structure-Activity Relationships for Prazosin and WB4101 Analogues as alpha1-Adrenoreceptor Antagonist.
[Articolo su rivista]
Giardin, D.; Bertini, R.; Brancia, E.; Brasili, Livio; Melchiorre, C.
abstract
Several a-adrenoreceptor antagonists were prepared by coupling one of the two moieties of WB 4101 (1) with oneof the two moieties of prazosin (2). Their blocking activity and relative selectivity on al- and a,-adrenoreceptorswere evaluated in the isolated rat vas deferens. Although retaining a significant selectivity toward al-adrenoreceptors,all the drugs were weaker antagonists than the parent compounds 1 and 2. Opening the piperazine ring of 2 gave3, which displayed a very high activity and selectivity toward a,-adrenoreceptors (a1/a2= 3890). This may haverelevance in understanding the mode of action of prazosin. In addition, 3 may represent a valuable tool in thecharacterization of a-adrenoreceptor subtypes.
1984
- 2-{[(2-(2,6-Dimethoxyphenoxy)ethyl]}-1,4-benzoxathiano:A New Antagonist With High Potency and Selectivity Toward alpha1-Adrenoreceptors.
[Articolo su rivista]
Melchiorre, C.; Brasili, Livio; Giardin, D.; Pigini, M.; Strappaghetti, G.
abstract
These results emphasize the importance of the position 4 in both thebenzodioxan and benzoxathian nucleus for the interactionat a,-adrenoreceptors. Since sulfur cannot form a productivehydrogen bond, the position 4 of antagonists bearinga benzodioxan or a benzoxathian nucleus would interactwith the receptor, either increasing the electron densityof the phenyl ring by a way of an electron-releasing effector giving rise to a dipole-dipole interaction.In conclusion, compound 1 is a potent and selectivealpha1-adrenoreceptor antagonist that may represent a valuabletool in the characterization of a-adrenoreceptor subtypes.
1984
- Correlation hetween adrenergic alpha-receptorantagonists of tetramine disulfidesand benzodioxanes classes
[Articolo su rivista]
Carlo, Melchiorre; Ugo, Gulini; Dario, Giardina'; Patrizia, Gallucci; Brasili, Livio
abstract
Symmetrical tetramine disulfides carrying on the terminal nitrogens one of the two moieties of WB 4101 (1), that is 1,4-benzodioxan-2-yl methyl or 2,6-dimethoxyphenoxyethyl substituents, were synthesized and their alpha-blocking activity evaluated on rat vas deferens preparations.3, haved as competitive a-antagonists at concentrations lower than 10 pM while being non competitive alpha-blockers at higher concentrations.However, their activity was significantly lower when compared to both I (competitive antagonism) and BHC (2) (irreversible blockade). The a1lcarbon analog 7 (two methylenes for the disulfide blidge of 3) was devoid of irreversible a-blocking activity while it displayed a high competitivealpha-blocking activity. This further supports the view that a covalent bond formation takes place between the tetramine disulfides and the adrenergicalpha-receptor.Furthermore, the introduction of the substituents on the two terminal nitrogens does not improve the activity of the unsubstituted tetramine disulfide9. This indicates that 1 can hardly interact with the binding site of the terminal nitrogens of 2. A possible interaction with the catecholaminebinding site is considered.
1984
- N,N"-(DITHIO-2,1-ETIIANEDIYL)BIS{N'-(PYRROL-2-YLMETI{YL)-1,6-HEXANEDIAMINE}(PYREXTRAMINE), A NEW IRREVERSIBLE a,.ADRENORECEPTOR BLOCKING AGENTTHE TETRAMINE DISULFIDE CLASS
[Articolo su rivista]
Brasili, Livio; EGLE BRANCIA, PIERO A. N. G. E. L. I.; Carlo, Melchiorre
abstract
In an attempt to further improve the a-adrenoreceptor blocking activity of benextramine, the effect of heteroaromaticsubstituents on the terminal nitrogens was studied. In this communication we report on the newly synthetizedN,N//-(dithio-2,1-ethanediyl)bis{N'-(pyrrol-2-ylmethyl)-1,6-hexanediamine} (pyrextramine) that displayed higher affinity(5-10-fold) and higher selectivity (about 12-fo1d) than benextramine. These preliminary results show thatpyrextramine can replace benextramine in the elucidation and characlerizatron of the peripheral ar-adrenoreceptors.
1984
- SYNTHESIS AND PHARMACOLOGICAL EVALUATIONOF SOME V/84101 ANALOGUES BEARING ANAPHTODIOXANIC NUCLEUS
[Articolo su rivista]
E., Castagnino; G., Strappaghetti; S., Corsano; P., Gallucci; Brasili, Livio; D., Giardina
abstract
Three WB4101 analogues, bearing system a 1,4-naphtodioxanic system, were svnthesized.. The decrease of alpha-blocking activity found for these compounds. showed that extension of aromatic area in the dioxanic mojety of such benzodioxanic deerivative, hinders the drug-receptor interaction.
1984
- Synthesis and alpha-blocl«ing activity of some cyclicand opened analogues of WB 4101 (-)
[Articolo su rivista]
Dario, Giardina'; Piero, Angeli; Brasili, Livio; Ugo, Gulini; Carlo, Melchiorre; Giovannella, Strappaghetti
abstract
The synthesis of some cyclic and opened analogues of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane (1, WB 4101) is described. The blocking activity of 1-5 was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens to investigate the structural requirements for competitive alpha-adrenoceptor occupancy by antagonists of the benzodioxane class. The activities of 1-5 at the presynapticalpha-adrenoceptor were not signiflcantly different whereas there were differences among the compounds of at least two orders of magnitudeat the postsynaptic alpha-adrenoceptor. This clearly indicates that the shuctural requirements at the presynaplic receptor level are less restriclive than those required by the postsynaptic alpha-adrenoceptor. The symmetric analogues 3 and 4 were significantly weaker postsynaplic alpha-antagonists compared to 1. On the other hand, 2 and 5 displayed a very high postsynaptic activity, almost comparable to that of 1. Thèse findingi might suggest that the antagonists of the benzodioxane class do not bind at two identical aromalic sites symmetrically arranged around the anionic site of the alpha-adrenoceptor. Indeed, they might indicate that the benzodioxane binding site(s) incorporates two areas with very similar but not identical strLrctural requirements. Furthermore, the very high activity of 5 may suggest that the benzodioxane nucleus is not essential to activity.
1983
- SYNTHESIS AND PHARMACOLOGICAL EVALUATIONOF PROPRANOLOL-CYCLIC ANALOGUES
[Articolo su rivista]
E., Castagnino; S., Corsano; G., Strappaghetti; Brasili, Livio; P., Gallucci
abstract
Three propranolol analogues' bearing the oxygen ol the-OH group enclosed in a 1,4-dioxanic ring system,were synthetized.The lack of beta-blocking activity found for these compounds demonstrates theimportant role played by a free -OHgroup in the drug-receptor interaction.
1982
- MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORS
[Articolo su rivista]
F., Gualtieri; Brasili, Livio; M., Giannella; M., Pigini
abstract
Several ethers and acetylderivatives of deoxamuscorine(l) and its isomers have been synthesized and tested to eyaluate the volumetricrequirements of the site interacting with the hydroxyl moiety ol the agonist(muscarinic subsite).
1982
- MOLECULAR. REQUIR.EMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORS
[Articolo su rivista]
Brasili, Livio; M., Leonelli; M., Giannella
abstract
Some cyclopentene derivatives lacking the oxygenatedlunctions have been sltnthesized and tested as cholinergic compounds. Theirgood muscarinic potency seems to confirm that such compounds interactwith a receptor area which is not coincident with that recognized by othercholinergic agents such as muscarine and deoxamuscarine.
1982
- Structural requirements for competitive s-adrenoceptor occupancy bycyclic and opened analogues of WB 4I0I
[Articolo su rivista]
Carlo, Melchiorre; Dario, Giardina'; Patrizia, Gallucci; Brasili, Livio
abstract
Modification of WB-4101 led to the discovery of several analogues with alpha adrenergic antagonist activity with comparable affinities.
1981
- MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORSXVI (x) - Synthesis qnd cholinergic activity ol 2- or 5-alkyl or 5-phenyl--4-methyl-3-oxo-1 -dimethylaminomethylcy clopentane methiodide.
[Articolo su rivista]
M., Pigini; Brasili, Livio
abstract
In order to study the cholinergic receptor through affinitychromatography, some derivatives ol deoxamuscarone (1 a) incorporating alkyl and phenyl substituents at the positions 2 and 5 were synthesizedas model compounds. However, the sharp drop in activity and the lack of discrimination between nicotinic and muicarinic receptors exhibited by thecompounds discourage their further development as affinity reagents
1981
- Molecular Requirements of the Active Site of CholinergicReceptors XV: Synthesis and Biological Activity of2, 3 -Dehydrodeoxamuscarone and 2,3 -Dehydrodeoxamuscarines
[Articolo su rivista]
Piero, Angeli; Brasili, Livio; Dario, Giardinà; Carlo, Melchiorre
abstract
To elucidate the molecular requirements of the activesites of cholinergic receptors, 3-methyl-4-oxo- 1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodide (2,3-dehydrodeoxamuscarone) andcis- and trons- 3-methyl-4-hydroxy-1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodides (cis- and trons-dehydrodeoxamuscarines)were synthesized and tested. The results, compared with those of thecorresponding oxygenated compounds, seem to indicate that 2,3-dehydrodeoxamuscarinesand muscarine bind at the same site while 2,3-dehydrodeoxamuscarone interacts with the site normally occupied bymuscarone. Furthermore, the previously suggested hypothesis that theunpolar site might somehow incorporate that of muscarone was considered.
1981
- Molecular properties of the adrenergic alpha-receptor6. - Optimum carbon chain-length between the inner nitrogenand the sulfur of tetramine disulfides
[Articolo su rivista]
Dario, Giardinà; Brasili, Livio; Carlo, Melchiorre; Bernard, Belleau; Bruno G., Benfey
abstract
"The recently reportod tetramine disu fides class of irreversible antagonists show a remarkable topographical dualism towards thealpha-receptor. Two series of alpha-antagonists were developed : the first carries benzyl-type substituents as in 24 or 26 and incorporates a six-carbon chain; the other incorporates an eight- or seven carbon chain but carries no substituent as in 22 or 21. However, onestructural feature was kept constant : the two-carbon chain between a sulfur and an inner nitrogen. In order to evaluate the possibleimportance of that reourring cystamine segment, compounds 5-18 (homologues of 22, 24 arrd 26) were synthesized and tested. Theywere all devoid of activity, thus suggesting that the cystamine moiety constitutes an important structural element for cr-blocking activityin the tetramine disulfides series of alha.blockers. The underlying drug-receptor interaction mechanisms are discussed.
1981
- Molecular properties of the adrenergic alpha-receptors.4.Topographical and structural differences betweentissue-specific binding sites as revealedby benextramine and analogues.
[Articolo su rivista]
Carlo, Melchiorre; Mario, Giannella; Brasili, Livio; Bruno G., Benfey; Bernard, Belleau
abstract
Until recently, it has been tacitly assurned that the postsynaptic or alpha1-adrenoreceptors of diverse biologicat origins are phar-macologicalll,similar. Quantitative evidence is now available that significant diiffcrences may exist between alpha1-adreceptors oi differenttissues and species. We submit experimental evidence which demonstrates that the alpha-receptor binding sites of the rat vas deferensand rabbit aorta or left atrium exhibit stereochemical and structural differences. Furthermore, the topographical dualism underling the respective effects oi Benextramine and AOC on rat vas deferens apply also to rabbit aorta. In addition, the tetraminedisulfides incorporating catechol nuclei showed high potency toward the alpha1-receptors of both rat vas deferens and rabbit aorta.Optimmm actìvity was sharply associatecl on both tissues with those 3'.4'-dihydroxybenzyl ccrnpouncls having a six- and eight-carbonchains. The mechanistic and topographicat significance of this dualism is discussed
1981
- Molecular requirements of the active sites of thecholinergic receptors XVII. 1,3-oxathiolane nucleus as a carrier of the active moeties
[Articolo su rivista]
Maria, Pigini; Brasili, Livio; Mario, Giannella; Fulvio, Gualtieri
abstract
In order to get infolmation on the molecular requirements of the cholinergic receptor, pure cis and, trans 2-methyl-5-dimethylaminomethyl-1,3-oxathiolane methiodide 2a-b and the corresponding sulfoxides 3a-b and sulfones 4a-b have synthesized and tested. Compound 2a was found to be very active, being 2 times more potent than muscarone and some 20 times more potent than Ach on Guinea Pig lleum, while 3a is equipotent with ACh on he same pràparation. The results of the pharmacological screening seem to suggest that 2a-b and 3a-d-interact with different subsite of the receptor.
1981
- Structural requirements for adrenergic alpha-receptorcovalent occupancy by chiral tetramine disulfides
[Articolo su rivista]
Brasili, Livio; Mario, Giannella; Carlo, Melchiorre; Bernard, Belleau; Bruno G., Benfey
abstract
Chiral tetramine disulfldes 3, designed to study the molecular properties of the active site of the adrenergic alpha-receptor, were synthesizedand tested on ral vas deferens preparation. The activity of the three optical isomers showed that the receptor displays an insignificantdegree ol stereoselectivity thus supporting the hypothesis that the benzylic groups of tetramine disulfides related to Benextramine donot bind at the same site that is normally occupied by the catechol nuclei of the neurotrirnsmitter. Rather, they would interact withan accessory area which appears to be insensitive to chirality efiects.
1980
- Irreversible alfa-adrenoceptor blocking effects and irreversible muscarinic blocking and nicotinic blocking effect of tetramine disulfides on heart B. G. Benfey, B. Belleau, L. Brasili, M. Giannella, C. Melchiorre
[Articolo su rivista]
B. G., Benfey; B., Belleau; Brasili, Livio; M., Giannella; C., Melchiorre
abstract
Inotropic effects of phenylephrine'-carbachol' and butyryrchorine were used in rabbit reft atrium to evaluate respectively, apha receptor blocking, muscarinic blocking and nicotinic blocking effect of tetramine disulfide. The alpha adrenergic blocking potency of newly synthetized derivatives were similar to those with an o-methoxy-benzyl group. Muscarinic and nicotinic blocking potency were correlated with the alpha adrenergic blocking potency.
1980
- MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORSXI - Synthesis and biological evaluation of isomuscarine and itsisomers
[Articolo su rivista]
M., Pigini; R., Ballini; F., Gualtieri; Brasili, Livio
abstract
The synthesis of isomuscarine (lI c) and ol its threeisomers is described. Their structure were establisked on the basis olN.M.R. and I.R. data.unlike the dioxolane (l), lrom which they are lormally derived bysubstituting the oxygen in position 3 by a CHOH group, the isomuscarinesare completely devoid of cholinergic activity. This result is explained bythe impossibility ol the corresponding receptor site of accepting a grouplarger than the ether oxygen. Interactions ol the onium and C-7 methylgroups are assumed to be the driving lorces for binding with the muscarinicreceptor while a dipole-dipole interaction for oxygenated functions is proposed
1980
- MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORSXII (*) - 3-Methyl-2-oxo-L-dimethylaminomethylcyclopentane methiodideas a new selective agonist for the nicotinic receptorM. GIANNELLA, P. ANGELI, C. MELCHIORRE, L. BRASILI
[Articolo su rivista]
M., Giannella; P., Angeli; C., Melchiorre; Brasili, Livio
abstract
To investigate further the nature of the active sites olcholinergic reeptors the carbocyclic analogs of isomuscarone and isomuscarine were synthesized- and tested for their cholinergicactivity.Like isomuscarines, such compounds are completely devoid of muscarinic activity which further support the hypothesis that the receptor site,corresponding to position 2 of the ring, cannot accept groups larger than and/or with a dipole having a different direction from that of an etheroxygen.on the other hand nicotinic activity is quite good. In this respectcompound (IV) is particulary interesting, being as actiie as ACh and pratically devoid of muscarinic aciivity.
1980
- Potentiation and inhibition ofnicotinic effects on striated muscle by the tetramlne disulfide benextramineB. G. Benfey, L. Brasili, C. Melchiorre, B. Belleau
[Articolo su rivista]
B. G., Benfey; Brasili, Livio; C., Melchiorre; B., Belleau
abstract
ln low concentratiuns the tetramlne disulfide benextramine potentiated the contracture of the isolated frog rectus abdominus muscle caused by acethilcholine but in presence of physiostigmine or in presence of higher concentration only inhibited the contracture by carbachol or butirrilcholine. The all-carbon analog of benextramine only inhibit the the effect of acetilcholine. The inhibitori effect of benextramine and it all-carbon analog were noncompèotitiveand ready reversible but the potentiating effect of benextramine was not readly reversible.
1980
- Reactivation by cysteamine of vascular alpha-adrenoceptors blocked by the tetraminedisulfide benextramine and interaction of benextramine with phenoxybenzamine
[Articolo su rivista]
Brasili, Livio; C., Melchiorre; B., Belleau; B. G., Benfey
abstract
The tetramine disulfide benextramine irreversibly blocked the noradrenaline-induced contraction of the isolated rabbit aorta in a manner similar to that observed with phenoxvbenzamine. Cysteamlne abolished abolished the benextramine blockade but not the phenoxybenzamine.Incubation of aortic tissue with benextramine prior to phenoxybenzamine exposure and follwed by cysteamine treatment led to a recovery of the noradrenaline response that depended on the dose of benextramine. Thus benextramine protected alpha adrenoceptors against phenoxybenzamine blockade.
1979
- THE CATECHOLAMINE Alpha--RECEPTOR AS A POLYANIONIC CYSTEINE PROTEIN.SELECTIVE COVALENT OCCUPANCY BY POLYAMINEDISULFIDES
[Relazione in Atti di Convegno]
Carlo, Melchiorre; MAN SEN, Yong; Bruno, Benfey; Brasili, Livio; Gordon, Bolger; Bernard, Belleau
abstract
Polyaminedisulfides represent a novel class of irreversible (non-equilibrium) antagonists of thealpha-adrenoreceptor. The following developments are presented: a) discovery of two distinct series oftetraminedisulfides each incorporating a unique member displaying optimum activity surpassingthat of a previous prototype by two orders of magnitude; b) unprecedented selectivity for thea-receptor as illustrated by lack of activity against the 5-hydroxytryptamine, the histamine andnicotinic receptors - however, some variable effects at high concentrations on some muscar.inicreceptors; c) unusual mechanism of o-receptor saturation suggestive of cooperative interactions; d)elucidation of the role of structural symmetry and dÌstribution on alpha-blocking activity anddeduction of topographical model for the active sites; e) discovery of a differentìal blockade ofNA- and A-elicited responses; f) possible role of multiple anionic sites in calcium binding; g)potentiating effect of certain tetramines on NA- and A-induced contractions; h) preliminaryconclusions on the molecular selectivity of the best prototype antagonist (BHC) made radioactivewith tritium.
1978
- MOLECULAR PROPERTIES OF THE ADRENERGIC a-RECEPTORIII - Origin of topographicol duqlism in the reaction of a receptor thiolwith symmetrical and unsymmetrical polyamine disulfides.
[Articolo su rivista]
C., Melchiorre; D., Giardina; Brasili, Livio; B., Belleau
abstract
structure actiuity relationship studies previously led tothe discovery of two distinct classes of tetramine-disulfides (l) and (II)each exhibiting optimum adrenergic alpha-blocking activity. The more potentone (l) was shown to uniquely discriminate between noradrenaline (NA)and adrenaline (A) binding sites. The unusual receptor topographical dualismtoward (l) and (ll) led to an investigation of the role of striclural symmetry in their interaction vvith the receptor. To this end, a series ol unsymmetricaldisulfide analogs (x-z) where half of (l) was retained and the otherhalf was made of unsubstituted N-(tr-aminoalkyl)cysteamines (I'l) and its homologs were synthesized and evaluated as alpha blockers. In addition the role ol the number of basic nitrogens on activity was also examined. It was found that the presence of four nitrogens is necessary for optimum activity. Moreover, it was diiscovered that optimum alpha-blockingpotency is obtained when the respective halves of the two best prototypes (I) and (II) ol symmetrical structures are fused compound (XVI) . Thisnew unsymmetrical tetramine disulftde has a potency approaching that of (l) and its receptor saturation mechanism is similar. Moreover, it also shares with (l) the ability to discriminate between NA and A eliciteil responses.The effect of methylation of a single inner nitrogen on potency allowed theconclusion that each hall of the unsymmetrical disulfide (XVI) respectively occupy hall of the sites for (l) and half of those for (ll). Accordingly, thepreviously observed topographical dualism toward (l) and (11) can best beaccommoclated by a model where two clistinct sets ol sites crossing eachother over the same receptor thiol are involved. The possible significance ofthe anionic site multiplicity of the alpha-receptor is briefly discussed.