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Dipartimento Scienze della Vita sede ex Scienze Farmaceutiche Via Campi 103

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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

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 - Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group [Articolo su rivista]
Linciano, P.; Pinzi, L.; Belluti, S.; Chianese, U.; Benedetti, R.; Moi, D.; Altucci, L.; Franchini, S.; Imbriano, C.; Sorbi, C.; Rastelli, G.

Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG. A series of derivatives decorated with different aromatic or heteroaromatic linkers, and various cap groups were synthesised and biologically tested. In vitro tests demonstrated that some compounds are able to inhibit HDAC6 with good potency, the best candidate reaching an IC50 of 700 nM. Such good potency obtained with a completely new ZBG make these compounds particularly attractive. The effect of the most active inhibitors on the acetylation levels of histone H3 and α- tubulin and their anti-proliferative activity of DU145 cells were also investigated. Docking studies were performed to evaluate the binding mode of these new derivatives and discuss structure-activity relationships.

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.

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.

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.

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 - Pharmacological properties and biochemical mechanisms of μ-opioid receptor ligands might be due to different binding poses: MD studies [Articolo su rivista]
Ronsisvalle, S.; Panarello, F.; Spadaro, A.; Franchini, S.; Pappalardo, M.; Guccione, S.; Basile, L.

Background: Central and peripheral analgesia without adverse effects relies on the identification of μ-opioid agonists that are able to activate 'basal' antinociceptive pathways. Recently developed μ-selective benzomorphan agonists that are not antagonized by naloxone do not activate G-proteins and β-arrestins. Which pathways do μ receptors activate? How can each of them be selectively activated? What role is played by allosteric binding sites? Methodology & results: Molecular modeling studies characterize the amino acid residues involved in the interaction with various classes of endogenous and exogenous ligands and with agonists and antagonists. Conclusions: Critical binding differences between various classes of agonists with different pharmacological profiles have been identified. MML series binding poses may be relevant in the search for an antinociception agent without side effects.

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.

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 - DAT atypical inhibitors as novel antipsychotic drugs [Poster]
Daini, Eleonora; Linciano, Pasquale; Sorbi, Claudia; Grilli, Massimo; Zoli, Michele; Franchini, Silvia; Vilella, Antonietta

Despite its classification as a psychiatric disease, schizophrenia is both a behavioral and a biological disorder resulting in neurocognitive dysfunction. Social and economic costs of schizophrenia are extremely high compared to its incidence and prevalence, however, due to a heterogeneous pattern of brain pathology and symptoms and to an unknown etiology, developing an effective treatment has been really challenging. Among the many neurochemical hypothesis, the dysregulation of dopaminergic neurotransmission has been considered as a central dogma of schizophrenia over the last few decades. In fact, patients with this pathology exhibit increased dopamine (DA) synthesis and release in the striatum which seems to correlate with positive symptoms and moreover, most of the effective antipsychotic drugs (APDs) are D2-receptor antagonists. Unfortunately, chronic treatment with APDs is associated with the induction of extrapyramidal side effects (EPS). In order to identify new possible APDs with a novel mechanism of action and potentially less EPS we tested 3 different compounds generated from the structural modification of vanoxerine (or GBR12909), a known atypical inhibitor of the presynaptic DA transporter (DAT) with cocaine-like activity but cardiotoxic properties that have precluded its clinical use. Preliminary in vitro studies showed that DAhLIs (DAT atypical inhibitors) are able to bind to DAT and inhibit DA reuptake. Additionally, our in vivo results showed that DAhLI i) have putative central effects, ii), unlike vanoxerine, reduce novelty-induced locomotor activity, and iii) counteract cocaine stimulating effects, suggesting that DAhLI may potentiate DA reuptake via DAT. These compounds may provide a way to reduce DA extracellular levels and DA neurotransmission with a selective action on active DA synapses, thus with reduced EPS typical of D2 antagonists, representing a new promising class of presynaptic APDs.

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.

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.

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

2019 - Molecular modeling and biological studies show that some μ-opioid receptor agonists might elicit analgesia acting as MMP-9 inhibitors [Articolo su rivista]
Ronsisvalle, S.; Spadaro, A.; Tomasello, B.; Basile, L.; Panarello, F.; Franchini, S.; Renis, M.; Guccione, S.; Crasci, L.; Panico, A. M.

Aim: Despite the serious side effects, analgesics acting on opioid receptors are still considered the best way to get antinociception. Matrix metalloproteinases, a large family of zinc-dependent proteases implicated in many pathological conditions, such as diabetes and osteoarthritis, are also involved in inflammation and pain. Methodology & results: Looking for evidence of possible interactions of opioid pathways and inflammation mediators, molecular modeling studies of a series of recently developed μ-opioid receptor benzomorphanic agonists together with biological data on pain and inflammation molecular targets, allowed us to hypothesize a possible correlation between μ-opioid receptor system and MMP-9. Conclusion: A new compound, (-)-MML1017, emerged as a possible dual-acting agent able to interact selectively and potently with the two molecular targets.

2019 - Multitarget 1,4-Dioxane Compounds Combining Favorable D 2 -like and 5-HT 1A Receptor Interactions with Potential for the Treatment of Parkinson's Disease or Schizophrenia [Articolo su rivista]
Del Bello, F.; Ambrosini, D.; Bonifazi, A.; Newman, A. H.; Keck, T. M.; Giannella, M.; Giorgioni, G.; Piergentili, A.; Cappellacci, L.; Cilia, A.; Franchini, S.; Quaglia, W.

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D 2 -like, 5-HT 1A , and α 1 -adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT 1A /D 4 agonism and D 2 /D 3 /5-HT 2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D 2 and as a potent full agonist at D 3 and D 4 subtypes. In addition to its potent 5-HT 1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT 1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

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.

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 - Constrained 1,4-dialkylpiperazines as monoamine transporters inhibitors for cocaine-related abuse [Poster]
Linciano, Pasquale; Franchini, Silvia; Sorbi, Claudia; Grilli, Massimo; Vallarino, Giulia; Kopajtic, Theresa; Michaelides, Mike; Katz, Jonathan L.; Brasili, Livio

Cocaine abuse and addiction remain grave health and societal problems with nearly 11,000 overdose deaths in 2015. Despite the high prevalence of cocaine use, no FDA-approved therapeutic for treating cocaine addiction has been achieved. The primary target for cocaine is dopamine transporter (DAT) and the rewarding and reinforcing effects of cocaine are mediated predominantly by its inhibition, with a consequent ‘reverse agonist’ effect. Several DAT inhibitors have been proposed as potential drugs for cocaine abuse.[1-2] One of the most studied DAT inhibitors, GBR12909 (Ki DAT = 3.7 nM), is able to slightly increase DA level and to blunt the cocaine-induced elevation of extracellular DA in vivo without exerting the central exciting effects of cocaine and addiction. Unfortunately, the phase I clinical trials failed, due to its cardiotoxicity.[3-4] In a lead optimisation program focused to identify novel and safe GBR12909 analogues, nine constrained derivatives were design and synthesized in a ligand based approach. Maintaining unaltered the fluoro-phenyl and phenylpropylpiperazine moiety, the rigidification of the ethylene ether, by means of tetrahydrofuran, dioxolane, dioxane, oxathiolane and dithiolane ring, was investigated in a focused SAR study (Fig. 1). All the compounds were assayed for the determination of the binding affinity for DAT, NET and SERT. In particular, two dioxolane derivatives displayed a binding affinity comparable to that of GBR12909, with Ki of 21.2 and 13.9 nM for DAT, and a selectivity ratio SERT/DAT > 30. Since the cyclization introduces one chiral centre, the two enantiomers of one racemic mixture were prepared following enantioselective synthetic procedures. The (R)- and (S)-forms showed a binding affinity comparable to the one determined for the racemate (Ki DAT of 16 and 46 nM, respectively), suggesting that the configuration of the stereocenters slightly affect the binding to the DAT transporter. For the most interesting derivatives, uptake inhibition assays were conducted in rat brain synaptosomes. It was observed that the potency trend parallel the affinity values.

2018 - Fluorometric detection of protein-ligand engagement: The case of phosphodiesterase5 [Articolo su rivista]
Di Rocco, Giulia; Martinelli, Ilaria; Pacifico, Salvatore; Guerrini, Remo; Cichero, Elena; Fossa, Paola; Franchini, Silvia; Cardarelli, Silvia; Giorgi, Mauro; Sola, Marco; Ponterini, Glauco

Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities. The new approach takes advantage of Förster Resonance Energy Transfer (FRET) between, as the donor, a fluorescein-like diarsenical probe able to covalently bind a tetracysteine motif fused to the recombinant PDE5 catalytic domain and, as the acceptor, a rhodamine probe covalently bound to the pseudosubstrate cGMPS. The FRET efficiency decreases when a competitive ligand binds the PDE5 catalytic site and displaces the cGMPS-rhodamine conjugate. We have structurally investigated the PDE5/cGMPS-rhodamine complex by molecular modelling and have used the FRET signal to quantitatively characterize its binding equilibrium. Competitive displacement experiments were carried out with tadalafil and cGMPS. An adaptation of the competitive-displacement equilibrium model yielded the affinities for PDE5 of the incoming ligands, nano- and micromolar, respectively.

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.

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

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

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

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

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

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

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

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

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

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 - ANTICANCER DRUGS [Brevetto]
Costantino, Luca; Costi, Maria Paola; Ponterini, Glauco; Marverti, Gaetano; Franchini, Silvia; Tondi, Donatella; D'Arca, Domenico; Ferrari, Stefania; Luciani, Rosaria; Venturelli, Alberto; Sammak, Susan; Lauriola, Angela; Gozzi, Gaia

Composti destabilizzanti l’omodimero timidilato sintasi

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

(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

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 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

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 - 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

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

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.

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 - 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

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 - 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

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 - Fragment Based Discovery of Thymidylate Synthase Dimeric Interface Inhibitors Through Mass Spectrometry. Invited lecture to the Fragment Based Lead Discovery track. [Relazione in Atti di Convegno]
Costi, Maria Paola; Ponterini, Glauco; Ferrari, Stefania; Costantino, Luca; Franchini, Silvia; Venturelli, Alberto; Genovese, Filippo

Fragment-based drug design has been applied to Thymidylate synthase.The strategy applied is Mass Spectrometry related. identification of small molecule library that can bind to the protein represents the starting point for further drug design of a novel class of TS inhibitors with high potential as anticancer agents.

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

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.

Costi, Maria Paola; Costantino, Luca; Sammak, Susan; Ponterini, Glauco; Ferrari, Stefania; Luciani, Rosaria; Farina, Davide Salvatore Francesco; Franchini, Silvia; Santucci, Matteo; Gabriele, Cruciani; Emanuele, Carosati

Oggetto del presente brevetto è una classe di prodotti chimici sintetizzati presso i laboratori del Dipartimento Scienze della Vita. Questi prodotti si sono dimostrati in grado di destabilizzare l’omodimero della timidilato sintasi umana, e sono i primi composti noti dotati di tale attività; quindi, come viene dettagliato nel testo del brevetto, rappresentano degli ottimi leads per lo sviluppo di farmaci antitumorali in possesso di un meccanismo di azione completamente nuovo.

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

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

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 - Unusual Targeting of the human Thymidylate synthase interface: a tethering approach with mass-spectrometric detection. [Relazione in Atti di Convegno]
Costi, Maria Paola; Franchini, Silvia; Ferrari, Stefania; R., Wade; S., Henrich; O., Salo; Genovese, Filippo; S., Mangani; Pozzi, Cristina; M., Santucci; Costantino, Luca; Sammak, Susan; G., Cruciani; E., Carosati; Ponterini, Glauco

Ovarian cancer is the fifth most common cause of death from cancer in women. The standard first-line treatment is a combination of paclitaxel and carboplatin (DDP) or carboplatin alone. In the case of progressive disease or drug resistance treatment with platinum, either alone or in combination, investigational compounds should be used (1). In the human ovarian carcinoma cell DDP-resistance was associated with cross-resistance to the thymidylate synthase (TS) inhibitor 5-fluorouracil (prodrug of 5FdUMP, fluorodeoxyuridine monophosphate) and methotrexate (2). We aim at restoring the sensibility to Platinum-based drugs through direct inhibition of Thymidylate synthase (TS) changing the mechanism of action from active site binders (classical TS inhibitors) to inhibitors of the regulatory function of monomeric TS through small molecule cellular perturbation. To this aim we applied a multidisciplinary approach to identify new molecules that could bind to specific pocket at the protein interface. We applied the tethering approach (3) that leads to the selection of disulfide compounds to anchor at the cystein on the monomeric interface (gray coloured balls on the left in the picture). Mass Spectrometry (MS) identification of the covalent TS-thiol complexes, and medicinal chemistry development of the identified hits (coloured structure on the right in the picture). We included cystein mutants design, site directed mutagenesis, disulfide library selection, tethering of thiol ligands at the protein interface through Mass spectrometry, X-ray crystallography, structure-based drug design and synthetic chemistry. The validation of the TS-interface inhibitor binders was accomplished trough FRET (Fluorescence resonance energy transfer) and enzyme kinetic assay. The strategies adopted and the midpoint/final results of the discovery processes will be presented. 1. Ozols RF et al. Lancet 2002;. 2. D.Cardinale et al, CMC, 2010, D.Cardinale et al, PNAS, 2011 ; 3. Stroud R et al PNAS 2000 and The project is supported by FP6 european grant (LIGHTS,, LSH 038752 and AIRC-DROC-2012(

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

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 - Allosteric Inhibition of human Thymidylate Synthase. [Abstract in Atti di Convegno]
S., Henrich; O., Salo Ahen; D., Garg; Cardinale, Daniela; Ferrari, Stefania; Franchini, Silvia; Genovese, Filippo; Guaitoli, Giambattista; Lazzari, Sandra; Venturelli, Alberto; S., Mangani; Costi, Maria Paola; R. C., Wade

Thymidylate synthase (TS) takes part in the folate pathway and is a dimeric enzyme that catalyzes the conversion from dUMP to dTMP. This reaction step is essential for all cells, but especially for fast growing cancer cells, making TS an important target for cancer treatment. Most of the clinical drugs for inhibiting TS are substrate or cofactor analogues that give rise to resistance after a certain time. The aim of the LIGHTS EU project is to overcome such resistance to inhibitors by interfering with TS dimerizationusing low molecular weight compounds and peptides binding to allosteric sites.

2010 - Cell-cycle Inhibition by Helicobacter pylori L-Asparaginase [Articolo su rivista]
C., Scotti; P., Sommi; M. V., Pasquetto; D., Cappelletti; S., Stivala; P., Mignosi; M., Savio; L. R., Chiarelli; G., Valentini; V. M., Bolanos Garcia; D. S., Merrell; Franchini, Silvia; M. L., Verona; C., Bolis; E., Solcia; R., Manca; D., Franciotta; A., Casasco; P., Filipazzi; E., Zardini; V., Vannini

Helicobacter pylori (H. pylori) is a major human pathogen causing chronic gastritis, peptic ulcer, gastric cancer, and mucosa associated lymphoid tissue lymphoma. One of the mechanisms whereby it induces damage depends on its interference with proliferation of host tissues. We here describe the discovery of a novel bacterial factor able to inhibit the cell-cycle of exposed cells, both of gastric and non-gastric origin. An integrated approach was adopted to isolate and characterise the molecule from the bacterial culture filtrate produced in a protein-free medium: size-exclusion chromatography, nonreducing gel electrophoresis, mass spectrometry, mutant analysis, recombinant protein expression and enzymatic assays. L-asparaginase was identified as the factor responsible for cell-cycle inhibition of fibroblasts and gastric cell lines. Its effect on cell-cycle was confirmed by inhibitors, a knockout strain and the action of recombinant L-asparaginase on cell lines.Interference with cell-cycle in vitro depended on cell genotype and was related to the expression levels of the concurrentenzyme asparagine synthetase. Bacterial subcellular distribution of L-asparaginase was also analysed along with its immunogenicity. H. pylori L-asparaginase is a novel antigen that functions as a cell-cycle inhibitor of fibroblasts and gastriccell lines. We give evidence supporting a role in the pathogenesis of H. pylori-related diseases and discuss its potential diagnostic application.

2010 - Design and characterization of a mutation outside the active site of human thymidylate synthase that affects ligand binding. [Articolo su rivista]
Cardinale, Daniela; O. M. H., Salo Ahen; Guaitoli, Giambattista; Ferrari, Stefania; Venturelli, Alberto; Franchini, Silvia; Battini, Renata; Ponterini, Glauco; R. C., Wade; Costi, Maria Paola

Due to its central role in DNA synthesis, human thymidylate synthase (hTS) is a well-established target for chemotherapeutic agents, such as fluoropyrimidines. The use of hTS inhibitors in cancer therapy is limited by their toxicity and the development of cellular drug resistance. Here, with the aim of shedding light on the structural role of the A-helix in fluoropyrimidine resistance, and we have created a fluoropyrimidine-resistant mutant by making a single point mutation, Glu30Trp. We postulated that residue 30, which is located in the A-helix, close to but outside the enzyme active site, could have a long-range effect on inhibitor binding. The mutant shows 100 times lower specific activity with respect to the wild-type hTS and is resistant to the classical inhibitor, FdUMP, as shown by a 6-fold higher inhibition constant. Circular dichroism experiments show that the mutant is folded. The results of molecular modeling and simulation suggest that the Glu30Trp mutation gives rise to resistance by altering the hydrogen-bond network between residue 30 and the active site.

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

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

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

not available

2010 - Tethering low affinity ligands to the dimeric interface of human thymidylate synthase. [Relazione in Atti di Convegno]
Costi, Maria Paola; Genovese, Filippo; Franchini, Silvia; Venturelli, Alberto; Lazzari, Sandra; Farina, Davide Salvatore Francesco; Pirondi, Silvia; R. C., Wade; S., Mangani; C., Pozzi; S., Henrich; Ferrari, Stefania; Ponterini, Glauco; Guaitoli, Giambattista; G., Cruciani


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

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

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

Not Available

2009 - MALDI-TOF MS as a tool for rapid Identification of Low Protein Affinity Drug Fragments. [Abstract in Atti di Convegno]
Genovese, Filippo; Lazzari, Sandra; G., Cruciani; Franchini, Silvia; S., Henrich; R. C., Wade; Venturelli, Alberto; Costi, Maria Paola


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


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

Not available

2008 - Merging disulphide bonds for drug design Interfering with a cancer key protein [Abstract in Atti di Convegno]
Lazzari, Sandra; Venturelli, Alberto; G., Cruciani; Franchini, Silvia; S., Henrich; Genovese, Filippo; R. C., Wade; Costi, Maria Paola


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

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 - Alternative strategies in medicinal chemistry to face drug resistance in anticancer therapy. [Abstract in Atti di Convegno]
Cardinale, Daniela; Ferrari, Stefania; Franchini, Silvia; Corsini, Enrico; Battini, Renata; Costi, Maria Paola


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


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


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

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


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.

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

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 Structure-Activity Relationships of 1-Aralkyl-4-Benzylpiperidine and 1-Aralkyl-4-Benzylpiperazine Derivatives as Potent sigma Ligands. [Articolo su rivista]
Costantino, Luca; Gandolfi, Francesca; Sorbi, Claudia; Franchini, Silvia; Prezzavento, O; Vittorio, F; Ronsisvalle, G; Leopardi, A; Poggesi, E; Brasili, Livio

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.

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

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.

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


2004 - C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. [Articolo su rivista]
Markiewski, M. M; Mastellos, D; Tudoran, R; Deangelis, R. A; Strey, C. W; Franchini, Silvia; Wetsel, R. A; Erdei, A; Lambris, J. D.

Although the complement system has been implicated in liver regeneration after toxic injury and partial hepatectomy, themechanism or mechanisms through which it participates in these processes remains ill-defined. In this study, we demonstrate thatcomplement activation products (C3a, C3b/iC3b) are generated in the serum of experimental mice after CCl4 injection and thatcomplement activation is required for normal liver regeneration. Decomplementation by cobra venom factor resulted in impairedentry of hepatocytes into S phase of the cell cycle. In addition, livers from C3-deficient (C3/) mice showed similarly impairedproliferation of hepatocytes, along with delayed kinetics of both hepatocyte hyperplasia and removal of injured liver parenchyma.Restoration of hepatocyte proliferative capabilities of C3/ mice through C3a reconstitution, as well as the impaired regeneration of C3a receptor-deficient mice, demonstrated that C3a promotes liver cell proliferation via the C3a receptor. These findings, together with data showing two waves of complement activation, indicate that C3 activation is a pivotal mechanism for liver regeneration after CCl4 injury, which fulfills multiple roles; C3a generated early after toxin injection is relevant during thepriming of hepatocytes, whereas C3 activation at later times after CCl4 treatment contributes to the clearance of injured tissue.

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

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 - Novel monoclonal antibodies against mouse C3 interfering with complement activation: description of fine specificity and applications to various immunoassays. [Articolo su rivista]
Mastellos, D; Prechl, J; Lszl, G; Papp, K; Olh, E; Argyropoulos, E; Franchini, Silvia; Tudoran, R; Markiewski, M; Lambris, J. D.; Erdei, A.

The role of complement proteins in various pathophysiological settings has been studied primarily using mouse models of disease. However, the specific contribution of C3-derived fragments to these biologic processes has not been addressed in a rigorous manner because of a lack of antibodies that can selectively recognize mouse C3 or any of its degradation fragments. Here we report the generation and characterization of a panel of rat monoclonal antibodies reacting with mouse C3 and its degradation products. We describe their performance in various immunological assays such as ELISA, Western blotting, flow cytometry and immunohistochemistry. Of all the antibodies generated, one selectively recognized the C3a anaphylatoxin, and all other reacted with C3c. Furthermore, two monoclonal antibodies preferentially reacted with the cleaved C3 fragments C3b/iC3b/C3c but not native C3. Except for the one recognizing C3a, all antibodies were suitable for detecting C3 deposited on cells and tissues, two effectively inhibited the hemolytic activity of mouse complement and one enhanced C3-deposition to the cell membrane. These novel monoclonal antibodies may serve as useful reagents for elucidating functions mediated by C3-derived fragments in various pathophysiological conditions.

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


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


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


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


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.

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 - Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. [Articolo su rivista]
Reca, R; Mastellos, D; Majka, M; Marquez, L; Ratajczak, J; Franchini, Silvia; Glodek, A; Marek, Honczarenko; M, Spruce; L., A; Janowska, Wieczorek; A, Lambris; J. D. AND RATAJCZAK M., Z.

Complement has recently been implicated in developmental pathways and noninflammatory processes. The expression of various complement components and receptors has been shown in a wide range of circulating myeloid and lymphoid cells, but their role in normal hematopoiesis and stem cell homing has notyet been investigated. We report that normal human CD34 cells and lineage differentiated hematopoietic progenitors express the complement anaphylatoxin C3a receptor (C3aR) and respond to C3a. Moreover, C3a, but not the biologically inactive desArg-C3a, induces calcium flux in these cells. Furthermore, we found thatC3 is secreted by bone marrow stroma and that, although C3a does not influence directly the proliferation/survival of hematopoietic progenitors, it (1) potentiates the stromal cell–derived factor 1 (SDF-1)– dependent chemotaxis of human CD34cells and lineage-committed myeloid, erythroid, and megakaryocytic progenitors; (2) primes SDF-1–dependent trans-Matrigel migration; and (3) stimulates matrix metalloproteinase-9 secretion and very late antigen 4 (VLA-4)–mediated adhesionto vascular cell adhesion molecule 1 (VCAM-1). Furthermore, we found that murine Sca-1 cells primed by C3a engrafted faster in lethally irradiated animals. These results indicate that normalhuman hematopoietic stem and progenitor cells express functional C3aR and that the C3aR-C3a axis sensitizes the responses of these cells to SDF-1 and thus may be involved in promoting their homing into the bone marrow via cross talkwith the SDF–CXC chemokine receptor-4 (CXCR4) signaling axis. C3a is the first positive regulator of this axis to be identified.

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


2002 - Monoclonal antibodies against mouse C3-fragments - a new repertoire of reagents targeting C3-mediated functions [Monografia/Trattato scientifico]
Erdei, A.; László, G.; Oláh, E.; Prechl, J.; Papp, K.; Argyropoulos, E.; Franchini, Silvia; Mastellos, D.; Lambris, J. D.

Monoclonal antibodies against mouse C3-fragments - a new repertoire of reagents targeting C3-mediated functions

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


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


2002 - The role of a newly-identified heterologous crosstalk between G-Protein coupled seven trasmembrane span receptors- Chemokine Receptor CXCR4 and Complement C3aR in Human hemato-lymphopoiesis and Innate Immunity [Abstract in Atti di Convegno]
Reca, R.; Majka, M.; Kijowski, J; Mastellos, D.; Franchini, Silvia; Lambris, J. D.; Ratajczak, M. Z.

The role of a newly-identified heterologous crosstalk between G-Protein coupled seven trasmembrane span receptors- Chemokine Receptor CXCR4 and Complement C3aR in Human hemato-lymphopoiesis and Innate Immunity

2001 - A novel role of complement: mice deficient in the fifth componenet of complement (C5) exhibit impaired liver regeneration. [Articolo su rivista]
Mastellos, D; Papadimitriou, J. C; Franchini, Silvia; Tsonis, P. A; Lambris, J. D.

Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly,complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations andanticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl4-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl4. In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2*-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.

2001 - Cloning and purification of the Rainbow Trout fifth component of complement (C5). [Articolo su rivista]
Franchini, Silvia; Zarkadis, K. I; Sfyroera, G; Sahu, A; Lambris, J. D.

To gain further insight into the evolutionary history of the complement proteins C3, C4, and C5 we have now cloned the fifthcomponent of complement from a rainbow trout (Oncorhynchus mykiss) liver cDNA library; this is the ®rst report of C5 cloningin a species other than human and mouse. The deduced amino acid sequence of a partial cDNA clone (2.25 kb), representingapproximately 44% of the coding sequence, showed 60 and 58% similarity to human and mouse C5, respectively. To validatethe molecular information derived from the cloning we developed an improved puri®cation protocol. Mass spectrometricanalysis of C5 tryptic digests yielded peptide signals that matched theoretical protein sequence derived from the partialcDNA. Northern blot analysis of RNA from various tissues showed the presence of a single mRNA transcript in trout liverand Southern blot analysis indicated that the gene coding for C5 is present as a single copy in the trout genome. The presence ofC5 in trout suggests that C3, C4, and C5 must have diverged before the appearance of teleost fish.

2001 - Kinetic Analysis of the Interactions of Complement Receptor 2(CR2, CD21) with Its Ligands C3d, iC3b, and the EBVGlycoprotein gp350/220 [Articolo su rivista]
Sarrias, M. R.; Franchini, Silvia; Canziani, G.; Argyropoulos, E.; Moore, W. T; Sahu, A.; Lambris, J. D.

The molecular mechanisms involved in the interaction of complement receptor 2 (CR2) with its natural ligands iC3b and C3d are still not well understood. In addition, studies regarding the binding site(s) of the receptor on C3 as well as the affinities of the C3 fragments for CR2 have produced contradictory results. In the present study, we have used surface plasmon resonance technology to study the interaction of CR2 with its ligands C3d, iC3b, and the EBV surface glycoprotein gp350/220. We measured the kinetics of binding of the receptor to its ligands, examined the influence of ionic contacts on these interactions, and assessed whether immobilized and soluble iC3b bound with similar kinetics to CR2. Our results indicate that 1) gp350 binding to CR2 follows asimple 1:1 interaction, whereas that of the C3 fragments is more complex and involves more than one intramolecular component;2) kinetic differences exist between the binding of C3d and iC3b to CR2, which may be due to an additional binding site foundon the C3c region of iC3b; and 3) iC3b binds to CR2 with different kinetics, depending on whether the iC3b is in solution or immobilized on the surface. These findings suggest that binding of CR2 to iC3b and C3d is more complex than previously thought.

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

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 - Characterization of factor H-like molecules in Rainbow Trout [Abstract in Atti di Convegno]
Zarkadis, K. I; Sfyroera, G; Franchini, Silvia; Sahu, A; Lambris, J. D.

Characterization of factor H-like molecules in Rainbow Trout

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

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


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

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.

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


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

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

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.