title: Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents.
abstract: Monoacylglycerol 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.
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beeské
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Leroy
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Redon
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Jacquet
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Françon
authors.affiliation: Exploratory Unit, Montpellier, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Bert
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Even
authors.affiliation: Therapeutic Strategic Unit Aging, Chilly-Mazarin, France.
authors.forename: Mati
authors.initials: M
authors.lastname: Lopez-Grancha
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tolstykh
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Brittain
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Arlt
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: He
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Bailin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Global Oncology Division, Cambridge, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertrand
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Houtmann
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: Alexey
authors.initials: A
authors.lastname: Rak
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: François
authors.initials: F
authors.lastname: Vallée
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Michot
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Augé
authors.affiliation: Therapeutic Strategic Unit Aging, Montpellier, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Menet
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Bergis
authors.affiliation: Therapeutic Strategic Unit Aging, Chilly-Mazarin, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.affiliation: Sanofi R&D, Exploratory Unit, Chilly-Mazarin, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Avenet
authors.affiliation: Lead Generation To Candidate Realization, Vitry-sur-Seine, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mikol
authors.affiliation: Exploratory Unit, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Didier
authors.affiliation: Exploratory Unit, Montpellier, France.
authors.forename: Johanna
authors.initials: J
authors.lastname: Escoubet
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005989:Glycerides / Q000737:chemistry / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects; D013058:Mass Spectrometry; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D012640:Seizures / Q000188:drug therapy / Q000473:pathology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; C000602434:SAR127303; D013449:Sulfonamides; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D000109:Acetylcholine; D000077285:Rimonabant