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Tricyclic pyrazoles. 3. Synthesis, biological evaluation, and molecular modeling of analogues of the cannabinoid antagonist 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6- tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide

Murineddu, Gabriele and Ruiu, Stefania and Loriga, Giovanni and Manca, Ilaria and Lazzari, Paolo and Reali, Roberta and Pani, Luca and Toma, Lucio and Pinna, Gérard Aimé (2005) Tricyclic pyrazoles. 3. Synthesis, biological evaluation, and molecular modeling of analogues of the cannabinoid antagonist 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6- tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide. Journal of Medicinal Chemistry, Vol. 48 (23), p. 7351-7362. eISSN 1520-4804. Article.

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DOI: 10.1021/jm050317f

Abstract

A series of analogues of 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 4a (NESS 0327) (Ruiu, S.; Pinna, G. A.; Marchese, G.; Mussinu, J. M.; Saba, P.; Tambaro, S.; Casti, P.; Vargiu, R.; Pani, L. Synthesis and characterization of NESS 0327: a novel putative antagonist of CB1 cannabinoid receptor. J. Pharmacol. Exp. Ther. 2003, 306, 363-370) was synthesized and evaluated for their affinity to cannabinoid receptors. Depending on the chemical modification of the lead structure that was chosen, compounds 4b, 4c, 4i, 4l, and 4m still proved to be potent binders of the CB1 receptor. Moreover, several analogues (4c, 4d, 4e, and 4m) demonstrated superior CB2 receptor binding affinities compared to the parent ligand. Compounds 4b, 4c, 4i, and 4l displayed the most promising pharmacological profiles, having the highest selectivity for CB1 receptors with Ki(CB2) to Ki(CB1) ratios of 11 250, 2000, 3330 and 4625, respectively. Compound 4c increased the intestinal propulsion in mice and antagonized the effect induced by the CB1 receptor agonist WIN 55,212-2. Finally, molecular modeling studies were carried out on a set of tricyclic pyrazoles (2a-4a) and on rimonabant 1 (SR141716A), indicating that high CB1 receptors affinities were consistent for the tricyclic derivatives, both with a nonplanar geometry of the tricyclic cores and with a precise orientation of the substituent (chlorine) on this ring system.

Item Type:Article
ID Code:415
Status:Published
Refereed:Yes
Uncontrolled Keywords:Piperidine derivatives, carboxamide, organic chlorine compounds, cannabinoid antagonist, molecular modeling, biological activity, chemical synthesis, CB1 cannabinoid receptor, tricyclic compound
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:American Chemical Society
eISSN:1520-4804
Deposited On:18 Aug 2009 10:02

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