Novel sterically hindered cannabinoid CB1 receptor ligands

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 CB 1 and CB 2 receptors. All compounds exhibited affinity for CB 1 and CB 2 receptors. Four compounds ( 4b , 9a , 9b , and 11a ) showed selectivity for CB 1 versus CB 2 receptors, although only the N -(3,3-diphenyl)propyl-2,2-diphenylacetamide ( 4b ) can be considered a potent CB 1 ligand ( K i = 58 nM). It was 140-fold selective over CB 2 receptors ( K i = 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 CB 1 ligands that, in view of its easy synthesis and high affinity for CB 1 receptors and despite its sterical hindrance, will be useful for the design of new blockers of this therapeutically exploitable receptor type.