title: Chemical probes of endocannabinoid metabolism.
abstract: The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics.
authors.affiliation: Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. jackie@abidetx.com
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000096:biosynthesis / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D008024:Ligands; D008994:Monoacylglycerol Lipases; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C078814:anandamide