Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands. (29th July 2017)

• Record Type: Journal Article
• Authors: Asproni, Battistina; Manca, Ilaria; Pinna, Giansalvo; Cichero, Elena; Fossa, Paola; Murineddu, Gabriele; Lazzari, Paolo; Loriga, Giovanni; Pinna, Gérard A.
• Is Part Of: Chemical biology & drug design. Volume 91:Number 1(2018)
• Page Start: 181
• Page End: 193
• Publication Date: 2017-07-29
• Subjects: binding affinity -- cannabinoid receptors -- docking studies -- pyrrolocycloalkylpyrazole; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13069
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Novel 1, 4‐dihydropyrazolo[3, 4‐ a ]pyrrolizine‐, 4, 5‐dihydro‐1 H ‐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‐1 H ‐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. Abstract : Novel 1, 4‐dihydropyrazolo[3, 4‐ a ]pyrrolizine‐, 4, 5‐dihydro‐1 H ‐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. Among all derivatives, 7‐chloro‐1‐(2, 4‐dichlorophenyl) ‐N‐ (homopiperidin‐1‐yl)‐4, 5‐dihydro‐1 H ‐pyrazolo[4, 3 ‐g ]indolizine‐3‐carboxamide (2j ) exhibited a 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 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.