Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents

Sci Rep. 2015 Jan 6;5:7642. doi: 10.1038/srep07642.

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.

MeSH terms

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

Substances

  • Analgesics
  • Arachidonic Acids
  • Cannabinoid Receptor Antagonists
  • Carbamates
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Piperidines
  • Pyrazoles
  • SAR127303
  • Sulfonamides
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Acetylcholine
  • Rimonabant