title: Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation.
abstract: Fatty acid amide hydrolase (FAAH) is an intracellular serine enzyme that catalyzes the hydrolysis of bioactive fatty acid ethanolamides such as anandamide and oleoylethanolamide (OEA). Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the effects of this endogenous cannabinoid agonist. Here, we show that systemic administration of the selective FAAH inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester; 0.3 mg/kg i.p.) increases anandamide levels in the brain of rats and wild-type mice but has no such effect in FAAH-null mutants. Moreover, URB597 enhances the hypothermic actions of anandamide (5 mg/kg i.p.) in wild-type mice but not in FAAH-null mice. In contrast, the FAAH inhibitor does not affect anandamide or OEA levels in the rat duodenum at doses that completely inhibit FAAH activity. In addition, URB597 does not alter the hypophagic response elicited by OEA (5 and 10 mg/kg i.p.), which is mediated by activation of peroxisome proliferator-activated receptor type-alpha. Finally, exogenously administered OEA (5 mg/kg i.p.) was eliminated at comparable rates in wild-type and FAAH-/- mice. Our results indicate that URB597 increases brain anandamide levels and magnifies anandamide responses by inhibiting intracellular FAAH activity. The results also suggest that an enzyme distinct from FAAH catalyzes OEA hydrolysis in the duodenum, where this lipid substance acts as a local satiety factor.
authors.affiliation: Department of Pharmacology, University of California, Irvine CA 92697-4625, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Fegley
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaetani
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002121:Calcium Channel Blockers; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009829:Oleic Acids; D047493:PPAR alpha; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C488250:oleoylethanolamide; C078814:anandamide