title: Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist.
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.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle, WA 98195-6540, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Luk
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Jin
authors.forename: Alexander
authors.initials: A
authors.lastname: Zvonok
authors.forename: Dai
authors.initials: D
authors.lastname: Lu
authors.forename: Xin-Zhong
authors.initials: XZ
authors.lastname: Lin
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D043884:Receptor, Cannabinoid, CB1