LY320135, a Novel Cannabinoid CB1 Receptor Antagonist, Unmasks Coupling of the CB1 Receptor to Stimulation of cAMP Accumulation

• Published in: The Journal of pharmacology and experimental therapeutics 1998-01, Vol.284 (1), p.291-297
• Main Authors: Felder, C C, Joyce, K E, Briley, E M, Glass, M, Mackie, K P, Fahey, K J, Cullinan, G J, Hunden, D C, Johnson, D W, Chaney, M O, Koppel, G A, Brownstein, M
• Format: Article
• Language: English
• Subjects: Animals; Benzofurans - pharmacology; Calcium Channels - drug effects; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Rats; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103

LY320135 is a selective antagonist for the brain CB1 receptor, having greater than 70-fold higher affinity for the CB1 than the peripheral CB2 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 μM, 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 μM) receptors, respectively. LY320135 functionally reversed anandamide-mediated adenylate cyclase inhibition in Chinese hamster ovary (CHO) cells stably expressing the CB1 receptor. Pertussis toxin treatment of CHO cells expressing the CB1 receptor attenuated the anandamide-mediated inhibition of adenylate cyclase and unmasked a stimulatory effect of anandamide on adenylate cyclase. The stimulatory component was blocked with LY320135. This compound also blocked WIN 55212–2-mediated inhibition of N-type calcium channels and activation of inwardly rectifying potassium channels in N18 and AtT-20-CB2 cells, respectively. LY320135 is a promising lead compound for the further development of novel, potent and selective cannabinoid antagonists of novel structure.