Identification of a Potent and Highly Efficacious, Yet Slowly Desensitizing CB1 Cannabinoid Receptor Agonist

Br J Pharmacol. 2004 Jun;142(3):495-500. doi: 10.1038/sj.bjp.0705792. Epub 2004 May 17.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Cannabinoid Receptor Modulators
  • Cannabinoids
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptor, Cannabinoid, CB1