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

Daniel K Nomura; Carolyn S S Hudak; Anna M Ward; James J Burston; Roger S Issa; Karl J Fisher; Mary E Abood; Jenny L Wiley; Aron H Lichtman; John E Casida

doi:10.1016/j.bmcl.2008.08.007

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

Daniel K Nomura, Carolyn S S Hudak, Anna M Ward, James J Burston, Roger S Issa, Karl J Fisher, Mary E Abood, Jenny L Wiley, Aron H Lichtman, John E Casida

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Bioorganic & medicinal chemistry letters
Volume	18
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2008.08.007
Publication status	Published - 15 Nov 2008

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10.1016/j.bmcl.2008.08.007

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title = "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.",

author = "Nomura, {Daniel K} and Hudak, {Carolyn S S} and Ward, {Anna M} and Burston, {James J} and Issa, {Roger S} and Fisher, {Karl J} and Abood, {Mary E} and Wiley, {Jenny L} and Lichtman, {Aron H} and Casida, {John E}",

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year = "2008",

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doi = "10.1016/j.bmcl.2008.08.007",

language = "English",

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T1 - Monoacylglycerol lipase regulates 2-arachidonoylglycerol action and arachidonic acid levels.

AU - Nomura, Daniel K

AU - Hudak, Carolyn S S

AU - Ward, Anna M

AU - Burston, James J

AU - Issa, Roger S

AU - Fisher, Karl J

AU - Abood, Mary E

AU - Wiley, Jenny L

AU - Lichtman, Aron H

AU - Casida, John E

N1 - DA003672, NIDA NIH HHS, United StatesES008762, NIEHS NIH HHS, United StatesP01 DA009789, NIDA NIH HHS, United StatesP01 DA009789-12A1, NIDA NIH HHS, United StatesR01 DA003672, NIDA NIH HHS, United StatesR01 DA003672-09, NIDA NIH HHS, United StatesR01 DA003672-24A1, NIDA NIH HHS, United StatesR01 ES008762-02, NIEHS NIH HHS, United States

PY - 2008/11/15

Y1 - 2008/11/15

N2 - 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.

AB - 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.

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DO - 10.1016/j.bmcl.2008.08.007

M3 - Article

C2 - 18752948

SN - 1464-3405

VL - 18

JO - Bioorganic & medicinal chemistry letters

JF - Bioorganic & medicinal chemistry letters

IS - 22

ER -

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

Abstract

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