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Franchini S.,University of Modena and Reggio Emilia | Baraldi A.,University of Modena and Reggio Emilia | Sorbi C.,University of Modena and Reggio Emilia | Pellati F.,University of Modena and Reggio Emilia | And 5 more authors.
MedChemComm | Year: 2015

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. This journal is © The Royal Society of Chemistry.

Del Bello F.,University of Camerino | Diamanti E.,University of Camerino | Giannella M.,University of Camerino | Mammoli V.,University of Camerino | And 9 more authors.
ACS Medicinal Chemistry Letters | Year: 2013

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that 3 or its (S)-enantiomer and 4, endowed with effective α2C-AR agonism/α2A-AR antagonism/5-HT1A-R agonism, or 7 and 9-11 producing efficacious α2C-AR agonism/α 2A-AR antagonism/I2-IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression. Such agents, lacking in sedative side effects due to their α2A-AR antagonism, might afford an improvement over current therapies with clonidine-like drugs. © 2013 American Chemical Society.

Franchini S.,University of Modena and Reggio Emilia | Battisti U.M.,University of Modena and Reggio Emilia | Prandi A.,University of Modena and Reggio Emilia | Tait A.,University of Modena and Reggio Emilia | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2016

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 Elsevier Masson SAS. All rights reserved.

Franchini S.,University of Modena and Reggio Emilia | Battisti U.M.,University of Modena and Reggio Emilia | Baraldi A.,University of Modena and Reggio Emilia | Prandi A.,University of Modena and Reggio Emilia | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2014

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 α1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α1 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 α1 or 5-HT1AR ligands. © 2014 Elsevier Masson SAS.

Anighoro A.,University of Modena and Reggio Emilia | Graziani D.,Recordati SpA | Bettinelli I.,Recordati SpA | Cilia A.,Recordati SpA | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Abstract Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors. © 2015 Elsevier Ltd.

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