Perspectives in Pharmacology Mechanisms of Endocannabinoid Inactivation: Biochemistry and Pharmacology

نویسندگان

  • ANDREA GIUFFRIDA
  • MASSIMILIANO BELTRAMO
  • DANIELE PIOMELLI
چکیده

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 include N-(4hydroxyphenyl)-arachidonylamide (AM404), which blocks transport with IC50 (concentration necessary to produce halfmaximal 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 antagonist N-(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. a-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. Cannabinoid receptors, the molecular targets of the active principle of cannabis D-tetrahydrocannabinol, are activated by a small family of naturally occurring lipids that include anandamide (arachidonylethanolamide) and 2-arachidonylglycerol (2-AG) (Devane et al., 1992; Di Marzo et al., 1994; Mechoulam et al., 1995; Sugiura et al., 1995; Stella et al., 1997). As in the case of other lipid mediators, these endogenous cannabis-like compounds (or “endocannabinoids”) may be released from cells upon demand by stimulus-dependent cleavage of membrane phospholipid precursors (Di Marzo et al., 1994). After release, anandamide and 2-AG may be eliminated by a two-step mechanism consisting of carrier-mediated transport into cells followed by enzymatic hydrolysis (Fig. 1). Because of this rapid deactivation process, the endocannabinoids may primarily act near their sites of synthesis by binding to and activating cannabinoid receptors on the surface of neighboring cells (for review, see Pertwee, 2000; Piomelli et al., 2000). The development of methods for endocannabinoid analysis (Giuffrida et al., 2000b; Schmid et al., 2000) and the availability of selective pharmacological probes for cannabinoid receptors (Pertwee, 2000) have allowed the exploration of the physiopathological functions served by the endocannabinoid system. Although still at their beginnings, these studies indicate that the endocannabinoids may significantly contribThe 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, g-aminobutyric acid; SHR, spontaneously hypertensive rats. 0022-3565/01/2981-7–14$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 298, No. 1 Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics 900025/911048 JPET 298:7–14, 2001 Printed in U.S.A. 7 at A PE T Jornals on Sptem er 2, 2017 jpet.asjournals.org D ow nladed from

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تاریخ انتشار 2001