Referenced in: none

Automatically associated channels: Kir2.3

Title: Conformationally constrained fatty acid ethanolamides as cannabinoid and vanilloid receptor probes.

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

Journal, date & volume: J. Med. Chem., 2009 May 14 , 52, 3001-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19361197

Abstract
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.