LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation

被引:0
作者
Felder, CC
Joyce, KE
Briley, EM
Glass, M
Mackie, KP
Fahey, KJ
Cullinan, GJ
Hunden, DC
Johnson, DW
Chaney, MO
Koppel, GA
Brownstein, M
机构
[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Div Neurosci, Indianapolis, IN 46285 USA
[2] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Div Endocrine, Indianapolis, IN 46285 USA
[3] NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA
[4] NIMH, Cell Biol Lab, Bethesda, MD 20892 USA
[5] Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA
[6] Univ Washington, Dept Physiol, Seattle, WA 98195 USA
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中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu 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, 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.
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页码:291 / 297
页数:7
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