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 interactions. 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_i CB₁ = 81 nm) and the highest CB₂ /CB₁ selectively ratio (>12). Docking studies carried out on such compounds were performed 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.

Keywords: binding affinity; cannabinoid receptors; docking studies; pyrrolocycloalkylpyrazole.