A Reversible and Selective Inhibitor of Monoacylglycerol Lipase Ameliorates Multiple Sclerosis |
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| Authors: | Dr. Gloria Hernández‐Torres Dr. Mariateresa Cipriano Erika Hedén Emmelie Björklund Dr. Ángeles Canales M. Sc. Debora Zian M. Sc. Ana Feliú Dr. Miriam Mecha Dr. Carmen Guaza Prof. Dr. Christopher J. Fowler Prof. Dr. Silvia Ortega‐Gutiérrez Prof. Dr. María L. López‐Rodríguez |
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| Affiliation: | 1. Department of Organic Chemistry I, Universidad Complutense de Madrid, 28040 Madrid (Spain) http://www.ucm.es/info/quimicamedica;2. Department of Pharmacology and Clinical Neuroscience, Ume? University, SE‐901 87 Ume? (Sweden);3. Cajal Institute, CSIC, Dr. Arce 37, 28002 Madrid (Spain) |
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| 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. |
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| Keywords: | endocannabinoids endogenous cannabinoid system enzyme inhibitors monoacylglycerol lipase multiple sclerosis |
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