Abstract
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 Ki values for LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and >10 μM, respectively. SimilarKi 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.
Footnotes
-
Send reprint requests to: Dr. Christian Felder, Eli Lilly Research Laboratories, Drop 0510, Lilly Corporate Center, Indianapolis, IN 46285.
-
↵1 The development of this study was supported in part by a SBIR Phase I grant DA09203. This study was also supported partly by the Keck Foundation, a McKnight Research Award, and National Institutes of Health grants NS01588, NS08174, and DA08934 (to K.P.M.).
- Abbreviations:
- THC
- (−)Δ9-tetrahydrocannabinol
- CHO
- Chinese hamster ovary
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- Received November 20, 1996.
- Accepted September 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
