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Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels.

ABSTRACT: 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 10mg/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.

SUBMITTER: Nomura DK

PROVIDER: S-EPMC2593629 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels.

Nomura Daniel K DK Hudak Carolyn S S CS Ward Anna M AM Burston James J JJ Issa Roger S RS Fisher Karl J KJ Abood Mary E ME Wiley Jenny L JL Lichtman Aron H AH Casida John E JE

Bioorganic & medicinal chemistry letters 20080806 22

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 10mg/kg intraperitoneally in mice. We find for the first time that MAGL activity is a major in vivo d ...[more]

PMID: 18752948

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