Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2arachidonoylglycerol (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 (IC 50 = 0.18 mm) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB 1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS. Figure 1. Representative irreversible MAGL inhibitors.

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… the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol, is a strategy for the treatment of multiple sclerosis. In their Communication on page 13765 ff., M. L. López-Rodríguez and co-workers describe a potent, reversible, and selective inhibitor of MAGL that slows the clinical progression of multiple sclerosis without inducing undesirable CB 1 -mediated side effect.