LY320135, A NOVEL CANNABINOID CB1 RECEPTOR ANTAGONIST, UNMASKS COUPLING OF THE CB1 RECEPTOR TO STIMULATION OF CAMP ACCUMULATION

LY320135 is a selective antagonist for the brain CB1 receptor, having greater than 70-fold higher affinity for the CB1 than the peripheral C B2 receptor. The K-i values for LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and >10 m u M, respectively. Similar K-i values were measured in binding studies performed on cerebellum and spleen membrane preparations endogenously expressing the CB1 (203 nM) and CB2 (>10 mu M) receptors, respectivel y. LY320135 functionally reversed anandamide-mediated adenylate cyclas e inhibition in Chinese hamster ovary (CHO) cells stably expressing th e CB1 receptor. Pertussis toxin treatment of CHO cells expressing the CB1 receptor attenuated the anandamide-mediated inhibition of adenylat e cyclase and unmasked a stimulatory effect of anandamide on adenylate cyclase. The stimulatory component was blocked with LY320135. This co mpound also blocked WIN 55212-2-mediated inhibition of N-type calcium channels and activation of inwardly rectifying potassium channels in N 18 and AtT-20-CB2 cells, respectively. LY320135 is a promising lead co mpound for the further development of novel, potent and selective cann abinoid antagonists of novel structure.