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Claudia SORBI

Ricercatore Universitario
Dipartimento Scienze della Vita sede ex Scienze Farmaceutiche Via Campi 103

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2023 - BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting [Articolo su rivista]
Sorbi, C.; Belluti, S.; Atene, C. G.; Marocchi, F.; Linciano, P.; Roy, N.; Paradiso, E.; Casarini, L.; Ronsisvalle, S.; Zanocco-Marani, T.; Brasili, L.; Lanfrancone, L.; Imbriano, C.; Di Rocco, G.; Franchini, S.

: The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer.

2023 - Discovery of potent pyrrolo-pyrimidine and purine HDAC inhibitors for the treatment of advanced prostate cancer [Articolo su rivista]
Moi, Davide; Bonanni, Davide; Belluti, Silvia; Linciano, Pasquale; Citarella, Andrea; Franchini, Silvia; Sorbi, Claudia; Imbriano, Carol; Pinzi, Luca; Rastelli, Giulio

2023 - Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status [Articolo su rivista]
Pinzi, L.; Bisi, N.; Sorbi, C.; Franchini, S.; Tonali, N.; Rastelli, G.

Tau is a protein characterized by large structural portions displaying extended conformational changes. Unfortunately, the accumulation of this protein into toxic aggregates in neuronal cells leads to a number of severe pathologies, collectively named tauopathies. In the last decade, significant research advancements were achieved, including a better understanding of Tau structures and their implication in different tauopathies. Interestingly, Tau is characterized by a high structural variability depending on the type of disease, the crystallization conditions, and the formation of pathologic aggregates obtained from in vitro versus ex vivo samples. In this review, we reported an up-to-date and comprehensive overview of Tau structures reported in the Protein Data Bank, with a special focus on discussing the connections between structural features, different tauopathies, different crystallization conditions, and the use of in vitro or ex vivo samples. The information reported in this article highlights very interesting links between all these aspects, which we believe may be of particular relevance for a more informed structure-based design of compounds able to modulate Tau aggregation.

2023 - Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents [Articolo su rivista]
Linciano, P.; Sorbi, C.; Rossino, G.; Rossi, D.; Marsala, A.; Denora, N.; Bedeschi, M.; Marino, N.; Miserocchi, G.; Dondio, G.; Peviani, M.; Tesei, A.; Collina, S.; Franchini, S.

Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-D-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone-and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases.

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 - Spiroxatrine derivatives towards 5-HT1A receptor selectivity [Articolo su rivista]
Sorbi, C.; Tait, A.; Battisti, U. M.; Brasili, L.

Background: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). Methods: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. Results: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a μM–nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. Conclusions: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2. Graphic abstract: [Figure not available: see fulltext.]

2019 - 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 - 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.

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.

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 - 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 - 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 - 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 and Structure-Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands [Articolo su rivista]
Corrado, Sandra; Battisti, Umberto M.; Sorbi, Claudia; Tait, Annalisa; Malfacini, Davide; Camarda, Valeria; Calò, Girolamo; Brasili, Livio

Several spiroxatrine derivatives were synthesized and evaluated as potential NOP receptor ligands. Structural modifications of the 1,4-benzodioxane moiety of spiroxatrine have been the focus of this research project. The structure–activity relationships that emerged indicate that the presence of an H-bond donor group (hydroxyl group) is more favorable for NOP activity when it is positioned a with respect to the CH2 linked to the 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives 4 and 22 show a moderately higher degree of stereoselectivity than trans isomers. In particular, the spiropiperidine derivative cis-4 has submicromolar agonistic activity, and it will be the reference compound for the design and synthesis of new NOP agonists.

2014 - Pyrrolidine Derivatives as New Ligands for 5-HT1A Receptors [Abstract in Atti di Convegno]
Sorbi, Claudia; Tait, Annalisa; Brasili, Livio

Our research group has long been involved in the development of new 5-HT1A selective ligands and 1,3-dioxolane derivatives bearing a phenoxyethylamine basic portion in position 4 were reported1. They were shown to have interesting 5-HT1A agonist activity accompanied by a good affinity, even if a certain alpha1 affinity was still present. 5-HT1A agonists and partial agonists have proved useful in the treatment of neuropsychiatric disorders such as anxiety and depression, to prevent neurodegeneration and for their antinociceptive activity2,3. On this basis and with the aim to improve 5-HT1A affinity and selectivity, compound A derivatives have been synthesized. A frozen structure of the ethylamine portion characterizes the new ligand and this variation4 with respect to the lead A has been designed in order to decrease the flexibility of this part of the molecule (figure 1). Stereospecific synthesis has been planned to give the desired four enantiomers (figure 1) so that it has been evaluated: 1. the effect on 5-HT1A affinity of the molecular rigidity provided by pyrrolidine core in comparison to that of the lead compound A; 2. stereoisomeric preferences for the receptor interaction. Several reactions and different synthetic schemes have been followed to obtained these four stereoisomers with good yield and a process optimization has been pursued. Structural characterization by NMR and mass (Q-TOF) analysis have been performed on the final compounds together with their optical purity determination.

2014 - Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors [Articolo su rivista]
Franchini, Silvia; Battisti, UMBERTO MARIA; Baraldi, Anna Maria; Prandi, Adolfo; Fossa, Paola; Cichero, Elena; Tait, Annalisa; Sorbi, Claudia; Marucci, Gabriella; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α<alpha>1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α<alpha>1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α<alpha>1 or 5-HT1AR ligands.

2014 - Synthesis, enantiomeric separation and docking studies of spiropiperidine analogues as ligands of the nociceptin/orphanin FQ receptor [Articolo su rivista]
Battisti, Umberto M.; Corrado, Sandra; Sorbi, Claudia; Cornia, Andrea; Tait, Annalisa; Malfacini, Davide; Cerlesi, Maria Camilla; Calò, Girolamo; Brasili, Livio

A series of triazospirodecanone derivatives were synthesized as potential NOP ligands. 8-(Chroman-4-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (4) and its 5-fluoro analogue (18) proved to be active as agonists with EC50 values in the submicromolar range. Single enantiomers of compound 4 were separated and tested as NOP agonists; the eutomer R-(+)-4 showed a pEC50 of 7.34. Finally docking studies were performed on the NOP receptor to identify the most significant stereospecific interactions.

2014 - Transacetalization of Acetals with Butane-1,2,4-triol Using Cobalt(II) Chloride and Chlorotrimethylsilane [Articolo su rivista]
Battisti, UMBERTO MARIA; Sorbi, Claudia; Franchini, Silvia; Tait, Annalisa; Brasili, Livio

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.

2014 - 1,4-Dioxolane-triazaspirodecanone derivatives as nociceptin/orphanin FQ receptor ligands [Articolo su rivista]
Corrado, Sandra; Sorbi, Claudia; Tait, Annalisa; Battisti, Umberto M.; Camarda, Valeria; Malfacini, Davide; Calò, Girolamo; Brasili, Livio

A series of N-substituted analogs based upon the spiropiperidine core of the lead compound Spiroxatrine was synthesized. In particular, the new compounds were obtained by replacing the benzodioxane moiety of the Spiroxatrine with several 2-substituted 1,3-dioxolanes. Thus the designed derivatives were synthesized and evaluated as possible NOP receptor ligands. As a conclusion of these studies, the new triazaspirodecanone derivatives showed unique and significant SAR as NOP receptor agonists. In particular, the present study demonstrated that 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one portion together with appropriate 1,3-dioxolane substituents could lead to a new promising class of NOP receptor ligands.

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, structural characterization and pharmacological evaluation of spiroxatrine analogs as potential nociceptin/orphanin FQ receptor ligands [Abstract in Atti di Convegno]
Corrado, Sandra; Battisti, Umberto; Sorbi, Claudia; Malfacini, Davide; Calò, Girolamo; Brasili, Livio; Tait, Annalisa

The nociceptin/Orphanin FQ (N/OFQ) peptide (NOP) receptor is a G protein-coupled receptor with a high degree of structural homology (~ 60%) to the classical opioid receptors μ, δ and κ. The interaction between NOPand its endogenous agonist N/OFQ plays a key role in pain transmission, among other biological functions. Therefore, this system opened a new option for the treatment of acute and chronic pain possibly by generating drugs with a lower side effect profile.The confirmed affinity towards NOP receptor of the α2 adrenergic and 5-HT1A partial agonist spiroxatrine (Ki= 127 nM) has led us to the synthesis of a series of novel and optimized analogs based upon the spiropiperidinecore, in order to perform preliminarySAR studies.

2011 - Synthesis and pharmacological evaluation of Spiroxatrine derivatives as potential ligands for NOP receptor [Abstract in Atti di Convegno]
Corrado, Sandra; Sorbi, Claudia; Manasieva, Leda; Camarda, Valeria; Calò, Girolamo; Brasili, Livio; Tait, Annalisa

Gli Atti del XXIV Congresso Nazionale della Società Chimica Italiana raccolgono gli abstract degli otre 1000 contributi scientifici del Congresso svoltosi a Lecce dall'11 al 16 settembre 2011. Il Congresso si articola in una sessione comune, con lectures tenute da ospiti prestigiosi (una menzione particolare meritano i 2 Nobel per la Chimica Jean-Marie Lehn e Kurt Wuthrich) e ben 12 sessioni parallele delle singole divisioni. Gli Atti contengono anche le schede dei docenti che saranno insigniti delle Medaglie della Società Chimica Italiana.

2011 - Synthesis and structural characterization of spiroxatrine derivatives as potential non-peptide ligands for NOP receptor [Abstract in Atti di Convegno]
Corrado, Sandra; Sorbi, Claudia; Brasili, Livio; Tait, Annalisa

Nociceptin or orphanin FQ peptide (N/OFQ) was identified in 1995 as the endogenous ligand for the opioid receptor ORL-1, actually denominated NOP, a fourth member of the classical μ, δ and κ opioid receptors family. N/OFQ-NOP system is implicated in several biological functions, such as in pain modulation. Therefore, NOP receptor represents an interesting target for the development of new therapeutical agentsagainst the acute cancer pain. On the basis of the confirmed affinity towards NOP receptor of the alpha2 adrenergic and 5-HT1A partial agonist spiroxatrine(Ki= 127 nM), we focused our attention on the design, synthesis and characterization of novel NOP receptor ligands with a spiropiperidine portion. The aim was to study the effects of some structural modifications on the 1,4-benzodioxane moiety ofspiroxatrine. In particular, we carried out: 1) isosteric replacement of C8 with a nitrogen atom; 2) disconnection of 1-8a and 4-4a bonds of spiroxatrine and of its nitrogen isosteres to give derivatives with a primary or a secondary alcoholic group respectively (2-5); 3) replacement of 1,4-benzodioxane moiety of spiroxatrine with a 1-benzhydryloxy-propan-2-ol and 2-benzhydryloxy-propan-1-ol moiety in order to increase the steric hindrance (6-7). Retrosynthetic strategies for compounds 1-7 are shown in the following schemes. Compounds 1-7 will be subjected to biological activity assays.

2010 - 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 - 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 - 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.

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


2009 - Synthesis of 6-O-methotrexylhyaluronan as a drug delivery system [Articolo su rivista]
Sorbi, Claudia; Bergamin, Massimo; Bosi, Susanna; Dinon, Francesca; Aroulmoji, Vincent; Khan, Riaz; Murano, Erminio; Norbedo, Stefano

Selective halogenation of hyaluronan and partial halogen substitution by methotrexate led to 6-chloro-6-deoxy-6-O-methotrexylhyaluronan, a potential antitumor drug. The remaining halogen could be further substituted by a second organic carboxylate, leading to mixed esters. 6-O-Acetyl-6-O-methotrexylhyaluronan and 6-O-butyryl-6-O-methotrexylhyaluronan were thus synthesized and characterized by NMR spectroscopy.

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 - (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.

2005 - Synthesis and structure-activity relationships of 1-aralkyl-4- benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent σ ligands [Articolo su rivista]
Costantino, Luca; Gandolfi, Francesca; Sorbi, Claudia; Franchini, Silvia; Prezzavento, O; Vittorio, F; Ronsisvalle, G; Leopardi, A; Poggesi, E; Brasili, Livio

In the attempt to define more accurately structure-affinity relationships for ó1 and ó2 ligands,we synthesized and tested on ó subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine,in which the effect of modifications on the aralkyl moiety was studied in a systematicway. The affinity of the compounds here described varied to a great extent, with a ó2/ó1selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative tobind to ó1 receptors in a different way than piperidines, we synthesized and tested a series ofpiperazine compounds; the comparison of their affinity with that of the correspondingpiperidines strongly supports the possibility of a different binding mode. While the compoundshere described are on the whole selective for ó vs serotonin 5-HT1A and dopamine D2 receptors,9aa, 9ba and 9ab possess a remarkable affinity for both ó and 5-HT1A receptors, with Ki inthe nanomolar range, and are selective with respect to D2 receptors. They displayed also apartial agonist profile in a human 5-HT1A [35S]GTPçS binding assay, suggesting their potentialuse as atypical antipsychotic agents.

2004 - 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


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 - (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


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 - 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


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 - 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