Abstract
Agonists at cannabinoid receptors, such as the phytocannabinoid Δ(9)-tetrahydrocannabinol, exert a remarkable array of therapeutic effects but are also associated with undesirable psychoactive side effects. Conversely, targeting enzymes that hydrolyze endocannabinoids (eCBs) allows for more precise fine-tuning of cannabinoid receptor signaling, thus providing therapeutic relief with reduced side effects. Here, we report the development and characterization of an inhibitor of eCB hydrolysis, UCM710, which augments both N-arachidonoylethanolamine and 2-arachidonoylglycerol levels in neurons. This compound displays a unique pharmacological profile in that it inhibits fatty acid amide hydrolase and α/β-hydrolase domain 6 but not monoacylglycerol lipase. Thus, UCM710 represents a novel tool to delineate the therapeutic potential of compounds that manipulate a subset of enzymes that control eCB signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Animals
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Arachidonic Acids / metabolism*
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COS Cells
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Cannabinoid Receptor Modulators / metabolism*
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Chlorocebus aethiops
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Endocannabinoids*
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Enzyme Inhibitors / pharmacology*
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Glycerides / metabolism*
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Mice
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Monoacylglycerol Lipases / antagonists & inhibitors*
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Monoacylglycerol Lipases / metabolism
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Nerve Tissue Proteins / antagonists & inhibitors*
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Nerve Tissue Proteins / metabolism
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Neurons / metabolism*
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Endocannabinoids
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Enzyme Inhibitors
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Glycerides
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Nerve Tissue Proteins
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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glyceryl 2-arachidonate
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ABHD6 protein, mouse
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Monoacylglycerol Lipases
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Amidohydrolases
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fatty-acid amide hydrolase
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anandamide