title: A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis.
abstract: Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18 μM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.
authors.affiliation: Department of Organic Chemistry I, Universidad Complutense de Madrid, 28040 Madrid (Spain) http://www.ucm.es/info/quimicamedica.
authors.forename: Gloria
authors.initials: G
authors.lastname: Hernández-Torres
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cipriano
authors.forename: Erika
authors.initials: E
authors.lastname: Hedén
authors.forename: Emmelie
authors.initials: E
authors.lastname: Björklund
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Canales
authors.forename: Debora
authors.initials: D
authors.lastname: Zian
authors.forename: Ana
authors.initials: A
authors.lastname: Feliú
authors.forename: Miriam
authors.initials: M
authors.lastname: Mecha
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009103:Multiple Sclerosis / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases
keywords: endocannabinoids; endogenous cannabinoid system; enzyme inhibitors; monoacylglycerol lipase; multiple sclerosis