Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist

Authors

  • Terry Luk,

    1. Department of Anesthesiology, University of Washington, Seattle, WA 98195-6540, U.S.A.
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  • Wenzhen Jin,

    1. Department of Pharmacology, University of Washington, Seattle, WA 98195-6540, U.S.A.
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  • Alexander Zvonok,

    1. Center for Drug Discovery and Departments of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, U.S.A.
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  • Dai Lu,

    1. Center for Drug Discovery and Departments of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, U.S.A.
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  • Xin-Zhong Lin,

    1. Center for Drug Discovery and Departments of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, U.S.A.
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  • Charles Chavkin,

    1. Department of Pharmacology, University of Washington, Seattle, WA 98195-6540, U.S.A.
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  • Alexandros Makriyannis,

    1. Center for Drug Discovery and Departments of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, U.S.A.
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  • Ken Mackie

    Corresponding author
    1. Department of Anesthesiology, University of Washington, Seattle, WA 98195-6540, U.S.A.
    2. Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-6540, U.S.A.
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Box 356540, HSB BB1428, Department of Anesthesiology, 1959 NE Pacific St., Seattle, WA 98195-6540, U.S.A. E-mail: kmackie@u.washington.edu

Abstract

  • 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

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