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Br J Pharmacol ; 142(3): 495-500, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15148260

ABSTRACT

1 The relationship of agonist efficacy to the rate of G protein-coupled receptor signaling desensitization is controversial. 2 Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic efficacy. 3 In this assay, the synthetic CB1 agonists, AM411, AM782, AM1902, AM2233 and WIN55,212-2 and the endogenous cannabinoid, 2-arachidonoyl ester, were full agonists. 4 The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2-arachidonoyl ether, and the phytocannabinoid, Delta9THC, were partial agonists. 5 The rate of desensitization of CB1 was independent of agonist efficacy. WIN55,212-2, AM782, AM1902, AM2233, and 2-arachidonoyl glycerol ester all desensitized quickly, with desensitization rates varying from 14% min(-1) to 10% min(-1). AM356, AM411, anandamide, and Delta9THC all desensitized considerably slower, at a rate of 5% min(-1). 6 Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Delta9THC. 7 CB1 agonist efficacy and rate of desensitization are not necessarily related.


Subject(s)
Cannabinoid Receptor Modulators/pharmacology , Cannabinoids/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Receptor, Cannabinoid, CB1/agonists , Animals , Dose-Response Relationship, Drug , Electrophysiology , G Protein-Coupled Inwardly-Rectifying Potassium Channels , Oocytes/drug effects , Oocytes/metabolism , Oocytes/physiology , Signal Transduction/drug effects , Xenopus laevis
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