title: The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review.
abstract: The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 87, Umeå, Sweden. christopher.fowler@umu.se.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D055808:Drug Discovery; D063388:Endocannabinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D058990:Molecular Targeted Therapy; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D050556:Fatty Acid-Binding Proteins; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases; C493412:FABP5 protein, human; C523108:NAAA protein, human
keywords: 2-Arachidonoylglycerol; Anandamide; Cyclooxygenase-2; Drug development; Fatty acid amide hydrolase; Monoacylglycerol lipase; Pain