Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand

Pharmacol Res. 2012 Aug;66(2):163-9. doi: 10.1016/j.phrs.2012.04.003. Epub 2012 Apr 14.


To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB₁ receptor with a K(i)=0.72 μM and selectivity vs. the CB₂ receptor (K(i)>10 μM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB₁ receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Animals
  • Binding, Competitive
  • Cannabinoid Receptor Modulators / metabolism
  • Endocannabinoids
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Humans
  • Ligands
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Piper*
  • Pyrans / chemical synthesis
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • Pyrones / chemical synthesis
  • Pyrones / chemistry
  • Pyrones / pharmacology*
  • Rats
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Structure-Activity Relationship


  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Enzyme Inhibitors
  • Ligands
  • Pyrans
  • Pyrones
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase