Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands

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_iCB₁ = 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.