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Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist
Author(s) -
Luk Terry,
Jin Wenzhen,
Zvonok Alexander,
Lu Dai,
Lin XinZhong,
Chavkin Charles,
Makriyannis Alexandros,
Mackie Ken
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705792
Subject(s) - agonist , cannabinoid receptor , anandamide , cannabinoid receptor agonists , cannabinoid , pharmacology , endocannabinoid system , desensitization (medicine) , chemistry , receptor , homologous desensitization , partial agonist , biology , biochemistry
The relationship of agonist efficacy to the rate of G protein‐coupled receptor signaling desensitization is controversial. 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. 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. The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2‐arachidonoyl ether, and the phytocannabinoid, Δ 9 THC, were partial agonists. 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 Δ 9 THC all desensitized considerably slower, at a rate of 5% min −1 . Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Δ 9 THC. CB1 agonist efficacy and rate of desensitization are not necessarily related.British Journal of Pharmacology (2004) 142 , 495–500. doi: 10.1038/sj.bjp.0705792