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Crystal structure of human mono-glyceride lipase in complex with SAR127303Crystal structure of human mono-glyceride lipase in complex with SAR127303
Structural highlights
FunctionMGLL_HUMAN Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth.[1] Publication Abstract from PubMedMonoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents. Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents.,Griebel G, Pichat P, Beeske S, Leroy T, Redon N, Jacquet A, Francon D, Bert L, Even L, Lopez-Grancha M, Tolstykh T, Sun F, Yu Q, Brittain S, Arlt H, He T, Zhang B, Wiederschain D, Bertrand T, Houtmann J, Rak A, Vallee F, Michot N, Auge F, Menet V, Bergis OE, George P, Avenet P, Mikol V, Didier M, Escoubet J Sci Rep. 2015 Jan 6;5:7642. doi: 10.1038/srep07642. PMID:25560837[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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