Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels

被引：75

作者：

Nomura, Daniel K. ^{[1
]}

Hudak, Carolyn S. S. ^{[1
]}

Ward, Anna M. ^{[1
]}

Burston, James J. ^{[2
]}

Issa, Roger S. ^{[1
]}

Fisher, Karl J. ^{[1
]}

Abood, Mary E. ^{[3
]}

Wiley, Jenny L. ^{[2
]}

Lichtman, Aron H. ^{[2
]}

Casida, John E. ^{[1
]}

机构：

[1] Univ Calif Berkeley, Environm Chem & Toxicol Lab, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA

[2] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA

[3] Temple Univ, Dept Anat & Cell Biol, Philadelphia, PA 19140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 22期

基金：

美国国家卫生研究院;

关键词：

Monoacylglycerol lipase inhibitors; 2-Arachidonoylglycerol; Arachidonic acid;

D O I：

10.1016/j.bmcl.2008.08.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC50 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. Published by Elsevier Ltd.

引用

页码：5875 / 5878

页数：4

共 18 条

[1] Isolation and expression of a mouse CB1 cannabinoid receptor gene - Comparison of binding properties with those of native CB1 receptors in mouse brain and N18TG2 neuroblastoma cells [J].