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 K_i(CB₂) to K_i(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.

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