Novel sterically hindered cannabinoid CB1 receptor ligands Original Research Article

In the present study, 11 novel N-(3,3-diphenyl)propyl-2,2-diphenylacetamide derivatives (4a–d and 9a–g) and six triphenylacetamides (10a–c and 11a–c) were synthesized and tested as ligands of cannabinoid CB1 and CB2 receptors. All compounds exhibited affinity for CB1 and CB2 receptors. Four compounds (4b, 9a, 9b, and 11a) showed selectivity for CB1 versus CB2 receptors, although only the N-(3,3-diphenyl)propyl-2,2-diphenylacetamide (4b) can be considered a potent CB1 ligand (Ki = 58 nM). It was 140-fold selective over CB2 receptors (Ki = 7800 nM) and behaved as an inverse agonist by stimulating forskolin-induced cAMP formation in mouse N18TG2 neuroblastoma cells. This compound is the first of a novel class of tetraphenyl CB1 ligands that, in view of its easy synthesis and high affinity for CB1 receptors and despite its sterical hindrance, will be useful for the design of new blockers of this therapeutically exploitable receptor type.