Current Medicinal Chemistry, 2010, 17, 2588-2607

A Review on the Monoacylglycerol Lipase: At the Interface Between Fat and Endocannabinoid Signalling

G. Labar1,2, J. Wouters2 and D.M. Lambert,1

1Université catholique de Louvain, Louvain Drug Research Institute, Cannabinoid and endocannabinoid research
group, Pharmaceutical Chemistry Dpt, Avenue E. Mounier 73.40, 1200 Brussels, Belgium
2Facultés universitaires Notre-Dame de la Paix, Faculté des Sciences, Laboratoire de Chimie biologique structurale,
rue de Bruxelles 61, 5000 Namur, Belgium

Abstract: Together with anandamide, 2-arachidonoylglycerol (2-AG) constitutes one of the main representatives of a
family of endogenous lipids known as endocannabinoids. These act by binding to CB1 and CB2 cannabinoid receptors, the
molecular target of the psychoactive compound ..9-THC, both in the periphery and in the central nervous system, where
they behave as retrograde messengers to modulate synaptic transmission.
These last years, evidence has accumulated to demonstrate the lead role played by the monoacylglycerol lipase (MAGL)
in the regulation of 2-arachidonoylglycerol (2-AG) levels. Considering the numerous physiological functions played by
this endocannabinoid, MAGL is now considered a promising target for therapeutics, as inhibitors of this enzyme could reveal
useful for the treatment of pain and inflammatory disorders, as well as in cancer research, among others.
Here we review the milestones that punctuated MAGL history, from its discovery to recent advances in the field of inhibitors
development. An emphasis is given on the recent elucidation of the tridimensional structure of the enzyme, which
could offer new opportunities for rational drug design.

Keywords: 2-arachidonoylglycerol, endocannabinoid system, monoacylglycerol lipase, monoglyceride lipase, inhibitor.