Discovery and Development of Endocannabinoid-Hydrolyzing Enzyme Inhibitors

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2- arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB1 and CB2 receptors, the molecular targets for Δ9-tetrahydrocannabinol (Δ9-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety. A variety of chemically diverse FAAH and MGL inhibitors have been developed and synthesized recently. Thus, this article reviews the scientific literature of various FAAH and MGL inhibitors presented during the past ten years.