Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands

Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands
Ilaria Manca, Giovanni Loriga, Elena Cichero, Giansalvo Pinna, Paolo Lazzari, Paola Fossa, Battistina Asproni, Gabriele Murineddu, Gérard A. Pinna
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nM, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nM. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (KiCB1 = 81 nM) and the highest CB2/CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed by using the hCB1 X-ray in complex with the close pyrazole analogue AM6538, and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands. This article is protected by copyright. All rights reserved. Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Among all derivatives, 7-chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited a good affinity for CB1 receptor (KiCB1 = 81 nM) and the highest CB2/CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed by using the hCB1 X-ray in complex with the close pyrazole analogue AM6538, and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13069

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