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Keywords:

  • Cannabinoid;
  • Xenopus;
  • desensitization;
  • efficacy;
  • potassium channel
  • 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, Δ9THC, 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 Δ9THC all desensitized considerably slower, at a rate of 5% min−1.

  • Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Δ9THC.

  • 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