Chapter 9: Natural and Synthetic Agents That Target Intracellular Monoacylglycerol Lipase (MGL) Activity

Monoacylglycerol lipase (MGL) is the main intracellular enzyme involved in the deactivation of 2-arachidonoyl-sn-glycerol (2-AG), the most abundant endocannabinoid present in the mammalian brain. MGL-mediated 2-AG hydrolysis is involved in a variety of physiological and pathological processes, including pain, inflammation, neuroprotection and cancer. The roles played by MGL in these processes and its potential exploitation as a therapeutic target fostered the search for compounds able to modulate MGL activity. The last two decades of research have led to the identification of several MGL inhibitors, with two compounds currently in clinical trials. In this chapter, we provide an overview of MGL structure, mechanism and actions, as well as of compounds affecting its activity. For the purpose of this review, MGL inhibitors are classified according to their origin (natural or synthetic) and mechanism of action (covalent or not). For each chemical class, we provide a detailed description of enzyme-inhibitor interactions, as revealed by structural and mutagenesis studies.