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Abstract
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.
© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
KEYWORDS:
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
- PMID: 32322464
- PMCID: PMC7161712
- DOI: 10.1016/j.apsb.2019.10.006
