CAY10499, a novel monoglyceride lipase inhibitor evidenced by an expeditious MGL assay.
Monoglyceride lipase (MGL) plays a major role in the metabolism of the lipid transmitter 2-arachidonoylglycerol (2-AG). This endocannabinoid is known to mediate a large number of physiological processes, and its regulation is thought to be of great therapeutic potential. However, the number of available monoglyceride lipase inhibitors is limited, mostly due to the lack of rapid and accurate pharmacological assays for the enzyme. We have developed a 96-well-format assay for MGL using a nonradiolabeled substrate, 4-nitrophenylacetate. The IC(50) values that were obtained for known inhibitors of MGL using 4-nitrophenylacetate were similar to those reported by using the radiolabeled form of an endogenous substrate, 2-oleoylglycerol. In a first small-scale screening, we identified CAY10499 as a novel monoglyceride lipase inhibitor. Thus, we report here the characterization of this submicromolar inhibitor, which acts on MGL through an unprecedented mechanism for inhibitors of this enzyme.
Unité de Chimie Pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université Catholique de Louvain, Avenue E. Mounier 73.40, 1200 Bruxelles, Belgium. giulio.muccioli@uclouvain.be
Giulio G
GG
Muccioli
Geoffray
G
Labar
Didier M
DM
Lambert
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D010648:Phenylacetates / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
C534918:CAY 10499; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010648:Phenylacetates; D011994:Recombinant Proteins; D008994:Monoacylglycerol Lipases; C118008:4-nitrophenylacetic acid