MAGL

Monoacylglycerol lipase (MAGL) is the principal enzyme degrading 2-arachidonoylglycerol (~85% of brain 2-AG hydrolysis), releasing arachidonic acid for downstream eicosanoid synthesis; MAGL thus sits at the intersection of the endocannabinoid and prostaglandin pathways. Characterization of its role in endocannabinoid signaling was established by Dinh et al. (2002, PNAS 99:10819). Selective MAGL inhibitors (JZL184 and clinical candidates such as ABX-1431/lu AG06466) elevate brain 2-AG, reduce neuroinflammation, and produce antinociceptive, anxiolytic, and anticonvulsant effects in rodent models. Chronic MAGL inhibition, however, can cause CB1 desensitization, a finding that has shaped development strategy toward partial or reversible inhibitors. Complementary enzymes ABHD6 and ABHD12 handle a minority share of 2-AG metabolism. → See also: 2-AG, FAAH, CB1 receptor.