Conformationally Constrained Fatty Acid Ethanolamides as Cannabinoid and Vanilloid Receptor Probes

Giovanni Appendino, Alessia Ligresti, Alberto Minassi, Maria Grazia Cascio, Marco Allara, Orazio Taglialatela-Scafati, Roger G Pertwee, Luciano De Petrocellis, Vincenzo Di Marzo

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

To investigate if certain acylethanolamides bind to both cannabinoid (CB1 and CB2) 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 CB1, CB2, and TRPV1 activity. Diastereodifferentiation between pairs of cis-trans isomers was observed only for TRPV1 activity, with poor enantiodifferentiation. Methylenation introduced (i) CB1 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 CB1/TRPV1 "hybrids" of potential therapeutic utility.

Original languageEnglish
Pages (from-to)3001-3009
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number9
Early online date10 Apr 2009
DOIs
Publication statusPublished - 14 May 2009

Keywords

  • sensory neurons
  • TRPV1 channels
  • VR1 receptor
  • anandamide
  • CB1
  • brain
  • arvanil
  • ligand
  • lipoxygenases
  • antagonist

Cite this

Appendino, G., Ligresti, A., Minassi, A., Cascio, M. G., Allara, M., Taglialatela-Scafati, O., ... Di Marzo, V. (2009). Conformationally Constrained Fatty Acid Ethanolamides as Cannabinoid and Vanilloid Receptor Probes. Journal of Medicinal Chemistry, 52(9), 3001-3009. https://doi.org/10.1021/jm900130m