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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Mechanisms of Endocannabinoid Inactivation: Biochemistry and Pharmacology

Andrea Giuffrida, Massimiliano Beltramo and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 7-14;
Andrea Giuffrida
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Massimiliano Beltramo
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Daniele Piomelli
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Abstract

The endocannabinoids, a family of endogenous lipids that activate cannabinoid receptors, are released from cells in a stimulus-dependent manner by cleavage of membrane lipid precursors. After release, the endocannabinoids are rapidly deactivated by uptake into cells and enzymatic hydrolysis. Endocannabinoid reuptake occurs via a carrier-mediated mechanism, which has not yet been molecularly characterized. Endocannabinoid reuptake has been demonstrated in discrete brain regions and in various tissues and cells throughout the body. Inhibitors of endocannabinoid reuptake includeN-(4-hydroxyphenyl)-arachidonylamide (AM404), which blocks transport with IC50 (concentration necessary to produce half-maximal inhibition) values in the low micromolar range. AM404 does not directly activate cannabinoid receptors or display cannabimimetic activity in vivo. Nevertheless, AM404 increases circulating anandamide levels and inhibits motor activity, an effect that is prevented by the CB1 cannabinoid antagonistN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A). AM404 also reduces behavioral responses to dopamine agonists and normalizes motor activity in a rat model of attention deficit hyperactivity disorder. The endocannabinoids are hydrolyzed by an intracellular membrane-bound enzyme, termed anandamide amidohydrolase (AAH), which has been molecularly cloned. Several fatty acid sulfonyl fluorides inhibit AAH activity irreversibly with IC50 values in the low nanomolar range and protect anandamide from deactivation in vivo. α-Keto-oxazolopyridines inhibit AAH activity with high potency (IC50 values in the low picomolar range). A more thorough characterization of the roles of endocannabinoids in health and disease will be necessary to define the significance of endocannabinoid inactivation mechanisms as targets for therapeutic drugs.

Footnotes

  • The financial support of the National Institute on Drug Abuse (under Grants 12447, 12413, and 12653) is gratefully acknowledged.

  • Abbreviations:
    2-AG
    2-arachidonylglycerol
    AAH
    anandamide amidohydrolase
    AM374
    palmitylsulfonyl fluoride
    AM404
    N-(4-hydroxyphenyl)-arachidonylethanolamide
    CNS
    central nervous system
    OEA
    oleylethanolamide
    PAG
    midbrain periaqueductal gray
    SR141716A
    N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
    GABA
    γ-aminobutyric acid
    SHR
    spontaneously hypertensive rats
    • Received November 2, 2000.
    • Accepted February 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Mechanisms of Endocannabinoid Inactivation: Biochemistry and Pharmacology

Andrea Giuffrida, Massimiliano Beltramo and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 7-14;

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Mechanisms of Endocannabinoid Inactivation: Biochemistry and Pharmacology

Andrea Giuffrida, Massimiliano Beltramo and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 7-14;
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