Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (path... More
Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors. Although a large number of MAGL inhibitors have been reported, novel inhibitors are still required, particularly reversible ones.
2-AG, 2-arachidonoyl glycerol, 2-Arachidaoylglycerol, 2-OG, 2-oleoylglycerol, 4-NPA, 4-nitrophenylacetate, 7-HCA, 7-hydroxycoumarinyl arachidonate, AA, arachidonic acid, ABHD6 and ABHD12, α/β-hydrolase 6 and 12, ABP, activity-based probes, ABPP, activity-based protein profiling, AD, Alzheimer's disease, AEA, anandamide, Arachidonic acid, BCRP, breast cancer resistant protein, CB1R and CB2R, cannabinoid receptors, CC-ABPP, click chemistry activity-based protein profiling, CFA, complete Freund's adjuvant, CNS, central nervous system, COX, cyclooxygenases, CYP, cytochrome P450 proteins, Cancer, DAG, diacylglycerol, DAGLs, diacylglycerol lipases, DTT, dithiothreitol, Drug discovery, EAE, encephalomyelitis, EI, enzyme–inhibitor complex, FAAH, amide hydrolase, FFAs, free fatty acids, FP, fluorophosphonate, FP-Rh, fluorophosphonate-rhodamine, FQ, fit quality, HFD, high-fat diet, HFIP, hexafluoroisopropyl, LC–MS, liquid chromatographic mass spectrometry, LFD, low-fat diet, MAGL, monoacylglycerol lipase, MAGs, monoglycerides, MS, multiple sclerosis, Metabolic syndrome, Monoacylglycerol lipases, NAM, N-arachidonoyl maleimide, NHS, N-hydroxysuccinimidyl, Neuroinflammation, OCT2, organic cation transporter 2, P-gp, P-glycoprotein, PA, phosphatidic acid, PD, Parkinson's disease, PET, positron emission tomography, PGE2, prostaglandin, PGs, prostaglandins, PK, pharmacokinetic, PLA2G7, phospholipase A2 group VII, SAR, structure–activity relationship, SBDD, structure-based drug design, SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis, THL, tetrahydrolipstatin, cPLA2, cytosolic phospholipase A2
