Chemistry & biology, 2007-12, Vol.14 (12), p.1357-1365
2007
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- Autor(en) / Beteiligte
- Titel
- URB602 Inhibits Monoacylglycerol Lipase and Selectively Blocks 2-Arachidonoylglycerol Degradation in Intact Brain Slices
- Ist Teil von
- Chemistry & biology, 2007-12, Vol.14 (12), p.1357-1365
- Ort / Verlag
- United States: Elsevier Ltd
- Erscheinungsjahr
- 2007
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 μM) 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 μM) 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-5521eISSN: 1879-1301DOI: 10.1016/j.chembiol.2007.10.017Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2225625
- Format
- –
- Schlagworte
- Animals, Arachidonic Acids - chemistry, Arachidonic Acids - metabolism, Arachidonic Acids - pharmacology, Biphenyl Compounds - chemistry, Biphenyl Compounds - pharmacology, Brain - drug effects, Brain - metabolism, Catalysis - drug effects, Cerebellum - drug effects, Cerebellum - metabolism, CHEMBIO, Endocannabinoids, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Ethanolamines, Glycerides - metabolism, HeLa Cells, Hippocampus - drug effects, Hippocampus - metabolism, Humans, Kinetics, Male, MOLNEURO, Monoacylglycerol Lipases - antagonists & inhibitors, Monoacylglycerol Lipases - genetics, Monoacylglycerol Lipases - metabolism, Organophosphonates - chemistry, Organophosphonates - pharmacology, Palmitic Acids - metabolism, Polyunsaturated Alkamides - metabolism, Rats, Rats, Wistar, Recombinant Proteins - chemistry, Recombinant Proteins - metabolism, Structure-Activity Relationship, Transfection