Volume 9, Issue 16 p. 2704-2710
Full Paper

CAY10499, a Novel Monoglyceride Lipase Inhibitor Evidenced by an Expeditious MGL Assay

Giulio G. Muccioli Dr.

Giulio G. Muccioli Dr.

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), Fax: (+32) 2-764-73-63

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Geoffray Labar

Geoffray Labar

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), Fax: (+32) 2-764-73-63

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Didier M. Lambert Prof. Dr.

Didier M. Lambert Prof. Dr.

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), Fax: (+32) 2-764-73-63

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First published: 28 October 2008
Citations: 82

Graphical Abstract

Novel and irreversible. We have developed a 96-well-format assay that uses a non-radiolabeled substrate, 4-nitrophenylacetate, to assess monoglyceride lipase (MGL) activity. IC50 values of known MGL inhibitors obtained by using this new substrate were found to be similar to those measured previously using a radiolabeled substrate. Additionally, in a screen for new MGL inhibitors, we identified CAY10499, a novel nanomolar MGL inhibitor that acts through an unprecedented mechanism of action.

Abstract

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 IC50 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.