Abstract
The N-aryl carbamate URB602 (biphenyl-3-ylcarbamic acid cyclohexyl ester) is an inhibitor of monoacylglycerol lipase (MGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Here, we investigated the mechanism by which URB602 inhibits purified recombinant rat MGL by using a combination of biochemical and structure-activity relationship (SAR) approaches. We found that URB602 weakly inhibits recombinant MGL (IC(50) = 223 +/- 63 microM) through a rapid and noncompetitive mechanism. Dialysis experiments and SAR analyses suggest that URB602 acts through a partially reversible mechanism rather than by irreversible carbamoylation of MGL. Finally, URB602 (100 microM) elevates 2-AG levels in hippocampal slice cultures without affecting levels of other endocannabinoid-related substances. Thus, URB602 may provide a useful tool by which to investigate the physiological roles of 2-AG and explore the potential interest of MGL as a therapeutic target.
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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Amides
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Animals
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Arachidonic Acids / chemistry
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Arachidonic Acids / metabolism*
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Arachidonic Acids / pharmacology
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Brain / drug effects*
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Brain / metabolism
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Catalysis / drug effects
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Cerebellum / drug effects
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Cerebellum / metabolism
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Endocannabinoids
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Ethanolamines
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Glycerides / metabolism*
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HeLa Cells
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Hippocampus / drug effects
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Hippocampus / metabolism
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Humans
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Kinetics
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Male
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Monoacylglycerol Lipases / antagonists & inhibitors*
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Monoacylglycerol Lipases / genetics
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Monoacylglycerol Lipases / metabolism
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Organophosphonates / chemistry
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Organophosphonates / pharmacology
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Palmitic Acids / metabolism
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Polyunsaturated Alkamides / metabolism
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Rats
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Rats, Wistar
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
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Transfection
Substances
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Amides
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Arachidonic Acids
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Biphenyl Compounds
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Endocannabinoids
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Enzyme Inhibitors
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Ethanolamines
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Glycerides
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Organophosphonates
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Palmitic Acids
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Polyunsaturated Alkamides
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Recombinant Proteins
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URB602
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methyl arachidonylfluorophosphonate
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palmidrol
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glyceryl 2-arachidonate
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Monoacylglycerol Lipases
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anandamide