Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands

Abstract

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 K_i values superior to 314 nM, whereas some of them showed moderate affinity for CB₁ receptor with K_i 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 (K_iCB₁ = 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.

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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 (K_iCB₁ = 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.

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