Abstract
Monoacylglycerol lipase (MAGL) is a key enzyme in the human endocannabinoid system. It is also the main enzyme responsible for the conversion of 2-arachidonoyl glycerol (2-AG) to arachidonic acid (AA), a precursor of prostaglandin synthesis. The inhibition of MAGL activity would be beneficial for the treatment of a wide range of diseases, such as inflammation, neurodegeneration, metabolic disorders and cancer. Here, the author reports the pharmacological evaluation of new disulfiram derivatives as potent inhibitors of MAGL. These analogues displayed high inhibition selectivity over fatty acid amide hydrolase (FAAH), another endocannabinoid-hydrolyzing enzyme. In particular, compound 2i inhibited MAGL in the low micromolar range. However, it did not show any inhibitory activity against FAAH.
Highlights
Monoacylglycerol lipase (MAGL) is a serine hydrolase ~33 kDa in size that catalyzes the hydrolysis of monoglycerides (MAGs) into glycerol and free fatty acids [1]
Disulfiram is a known and potent irreversible inhibitor of MAGL, and it showed an IC50 in the micromolar range, in agreement with the values reported in the literature [16]
Introducing polar functional groups like hydroxyl (2e) or carboxylate (2f) onto the two ethyl groups of disulfiram seemed to be beneficial for the anti-MAGL activity
Summary
Monoacylglycerol lipase (MAGL) is a serine hydrolase ~33 kDa in size that catalyzes the hydrolysis of monoglycerides (MAGs) into glycerol and free fatty acids [1]. Its substrates include MAGs of different fatty acid chain lengths and degrees of saturation (e.g., 2-arachidonoyl glycerol, 2-oleylglycerol, 2-palmitoylglycerol, and 2-stearoylglycerol), but 2-arachidonoyl glycerol (2-AG) is of particular pharmacological importance because it is one of the most abundant endocannabinoids capable of activating both the CB1R and CB2R types of cannabinoid receptors [2]. The inhibition of MAGL will enhance endocannabinoid signaling and reduce eicosanoid production [7]. The endocannabinoid system is associated with metabolic disorders. MAGL inhibition represents a plausible strategy for the treatment of metabolic disorders [2]
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