Conformationally constrained fatty acid ethanolamides as cannabinoid and vanilloid receptor probes

J Med Chem. 2009 May 14;52(9):3001-9. doi: 10.1021/jm900130m.


To investigate if certain acylethanolamides bind to both cannabinoid (CB(1) and CB(2)) and vanilloid TRPV1 receptors because of their conformational flexibility, we introduced a methylene lock on their ethanolamine "head", thereby generating a cyclopropane ring with two stereogenic centers and chiral cis/trans diastereomers with different topology of presentation to binding sites. After resolution by chiral-phase HPLC, diastereo- and enantiopure arachidonoyl-, oleoyl-, and palmitoylcyclopropanolamides were tested in assays of CB(1), CB(2), and TRPV1 activity. Diastereodifferentiation between pairs of cis-trans isomers was observed only for TRPV1 activity, with poor enantiodifferentiation. Methylenation introduced (i) CB(1) receptor affinity in oleoylethanolamide while increasing in a diastereoselective way its activity at TRPV1 and (ii) strong diastereoselective activity at TRPV1, but not cannabinoid, receptors in the otherwise inactive palmitoylethanolamide. These results show that the N-alkyl group of acylethanolamides has a different role in their interaction with cannabinoid and vanilloid receptors and that acylcyclopropanolamides qualify as CB(1)/TRPV1 "hybrids" of potential therapeutic utility.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / metabolism*
  • Animals
  • Cell Line
  • Fatty Acids / chemistry*
  • Humans
  • Ligands
  • Molecular Conformation*
  • Protein Binding
  • Receptors, Cannabinoid / metabolism*
  • Stereoisomerism
  • Substrate Specificity
  • TRPV Cation Channels / metabolism*


  • Amides
  • Fatty Acids
  • Ligands
  • Receptors, Cannabinoid
  • TRPV Cation Channels