URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices.
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.
King
Alvin R
AR
Department of Pharmacology, University of California, Irvine, Irvine, CA 92697, USA.
Duranti
Andrea
A
Tontini
Andrea
A
Rivara
Silvia
S
Rosengarth
Anja
A
Clapper
Jason R
JR
Astarita
Giuseppe
G
Geaga
Jennifer A
JA
Luecke
Hartmut
H
Mor
Marco
M
Tarzia
Giorgio
G
Piomelli
Daniele
D
D000577:Amides; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004983:Ethanolamines; D005989:Glycerides / Q000378:metabolism*; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology; D010169:Palmitic Acids / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D000577:Amides; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D005989:Glycerides; D063065:Organophosphonates; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D011994:Recombinant Proteins; C501835:URB602; C104810:methyl arachidonylfluorophosphonate; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C078814:anandamide