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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arachidonic Acid / analysis*
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Arachidonic Acid / metabolism
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Arachidonic Acids / analysis*
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Arachidonic Acids / metabolism
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Brain / drug effects*
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Brain / enzymology
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Cell Membrane / drug effects
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Endocannabinoids
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Glycerides / analysis*
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Glycerides / metabolism
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Inhibitory Concentration 50
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Mice
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Molecular Structure
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Monoacylglycerol Lipases / antagonists & inhibitors*
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Monoacylglycerol Lipases / metabolism
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacology
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Receptor, Cannabinoid, CB1 / metabolism
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Structure-Activity Relationship
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Sulfur Compounds / chemistry
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Sulfur Compounds / pharmacology
Substances
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Arachidonic Acids
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Endocannabinoids
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Glycerides
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Organophosphorus Compounds
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Receptor, Cannabinoid, CB1
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Sulfur Compounds
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Arachidonic Acid
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glyceryl 2-arachidonate
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Monoacylglycerol Lipases