Novel sterically hindered cannabinoid CB sub(1) receptor ligands

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 15; pp. 7510 - 7515
• Main Authors: Urbani, Paolo, Cascio, Maria Grazia, Ramunno, Anna, Bisogno, Tiziana, Saturnino, Carmela, Di Marzo, Vincenzo
• Format: Journal Article
• Language: English
• Published: 01-08-2008
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.06.001

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