title: Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons.
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.
authors.affiliation: Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington 98195-7270.
authors.forename: William R
authors.initials: WR
authors.lastname: Marrs
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Horne
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutierrez
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Cisneros
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Cong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Yi Hsing
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Bioanalysis and Pharmacology of Bioactive Lipids Laboratory, CHAM7230, Louvain Drug Research Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium, and.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Lopez-Rodriguez
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280,; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195-6560. Electronic address: nstella@uw.edu.
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D019556:COS Cells; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002522:Chlorocebus aethiops; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism*; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C527261:ABHD6 protein, mouse; C078814:anandamide