Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Sci Rep ; 5: 7642, 2015 Jan 06.
Article in English | MEDLINE | ID: mdl-25560837

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.


Subject(s)
Analgesics/pharmacology , Arachidonic Acids/metabolism , Carbamates/pharmacology , Endocannabinoids/metabolism , Glycerides/metabolism , Learning/drug effects , Memory, Short-Term/drug effects , Monoacylglycerol Lipases/metabolism , Sulfonamides/pharmacology , Acetylcholine/metabolism , Administration, Oral , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Arachidonic Acids/chemistry , Binding Sites , Brain/metabolism , Cannabinoid Receptor Antagonists/pharmacology , Carbamates/chemistry , Carbamates/therapeutic use , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Disease Models, Animal , Electric Stimulation , Endocannabinoids/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glycerides/chemistry , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Hydrolysis , In Vitro Techniques , Long-Term Potentiation/drug effects , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, SCID , Monoacylglycerol Lipases/antagonists & inhibitors , Pain/drug therapy , Pain/pathology , Piperidines/pharmacology , Protein Structure, Tertiary , Pyrazoles/pharmacology , Rimonabant , Seizures/drug therapy , Seizures/pathology , Sulfonamides/chemistry , Sulfonamides/therapeutic use
SELECTION OF CITATIONS
SEARCH DETAIL
...