title: Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis--comparison with effects upon fatty acid amide hydrolase.
abstract: A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) were synthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid amide hydrolase activities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits that mimic the glycerol fragment. This series has allowed us to carry out the first systematic structure-activity relationship study on inhibition of 2-AG hydrolysis. The most promising compounds were oxiran-2-ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2-ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 muM, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26 muM, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 muM, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolytic activity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.
authors.affiliation: Departamento de Química OrgAnica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Cisneros
authors.forename: Séverine
authors.initials: S
authors.lastname: Vandevoorde
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Clément
authors.initials: C
authors.lastname: Paris
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D063388:Endocannabinoids; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D050178:Monoglycerides / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004852:Epoxy Compounds; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D050178:Monoglycerides; D053284:Polyunsaturated Alkamides; D011714:Pyrans; D000099252:Fatty Acid Amide Hydrolases; C524186:oxiran-2-ylmethyl eicosa-5,8,11,14-tetraenoate; C524187:tetrahydro-2H-pyran-2-ylmethyl eicosa-5,8,11,14-tetraenoate; C094503:glyceryl 2-arachidonate; C505247:2-oleoylglycerol; C078814:anandamide