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.
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.
Murineddu
Gabriele
G
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
Ruiu
Stefania
S
Loriga
Giovanni
G
Manca
Ilaria
I
Lazzari
Paolo
P
Reali
Roberta
R
Pani
Luca
L
Toma
Lucio
L
Pinna
Gérard A
GA
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006575:Heterocyclic Compounds, 3-Ring; C475771:N-piperidinyl-(8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo(6,7)cyclohepta(1,2-c)pyrazole-3-carboxamide); D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2