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Vol. 298, Issue 1, 7-14, July 2001
Department of Pharmacology, University of California, Irvine,
California (A.G., D.P.); and Schering-Plough Research Institute, San
Raffaele Science Park, Milan, Italy (M.B.)
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-(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 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. 
-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.
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