Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3831-7. doi: 10.1016/j.bmcl.2016.06.076. Epub 2016 Jun 27.

Abstract

2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the cannabinoid receptors type 1 and 2. It also serves as an important lipid precursor for the eicosanoid signaling pathway. Consequently, 2-AG is involved in many physiological functions, including anxiety, food intake, inflammation, memory, pain sensation and neurotransmission. Diacylglycerol lipases (DAGLs) are the main biosynthetic enzymes for 2-AG and their role in several pathophysiological conditions is currently under investigation. In this Digest we review all DAGL inhibitors reported to date and their effects in preclinical models of neurodegeneration and metabolic disorders.

Keywords: 2-Arachidonoylglycerol; Diacylglycerol lipases; Drug development; Metabolic syndrome; Neurodegenerative diseases; Neuroinflammation; Obesity.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Endocannabinoids / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / therapeutic use
  • Glycerides / metabolism
  • Humans
  • Lipoprotein Lipase / antagonists & inhibitors*
  • Lipoprotein Lipase / metabolism
  • Metabolic Diseases / drug therapy
  • Metabolic Diseases / metabolism
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Protein Binding
  • Receptors, Cannabinoid / deficiency
  • Receptors, Cannabinoid / genetics
  • Receptors, Cannabinoid / metabolism
  • Signal Transduction
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Receptors, Cannabinoid
  • Small Molecule Libraries
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase