Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels

Potent MAGL inhibitors in mice elevate 2-AG and correspondingly lower AA levels in some but not in all tissues. Apparent direct OP displacement of CB1 agonist binding may be due instead to 2-AG in brain membranes which is metabolically stabilized by MAGL inhibition. The structure–activity relationships of organophosphorus (OP) and organosulfur compounds were examined in vitro and in vivo as inhibitors of mouse brain monoacylglycerol lipase (MAGL) hydrolysis of 2-arachidonoylglycerol (2-AG) and agonist binding at the CB1 receptor. Several compounds showed exceptional potency toward MAGL activity with IC 50 values of 0.1–10 nM in vitro and high inhibition at 10 mg/kg intraperitoneally in mice. We find for the first time that MAGL activity is a major in vivo determinant of 2-AG and arachidonic acid levels not only in brain but also in spleen, lung, and liver. Apparent direct OP inhibition of CB1 agonist binding may be due instead to metabolic stabilization of 2-AG in brain membranes as the actual inhibitor.