Conformationally constrained fatty acid ethanolamides as cannabinoid and vanilloid receptor probes.
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.
Appendino
Giovanni
G
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Novara, Italy. Giovanni.Appendino@pharm.unipmn.it
Ligresti
Alessia
A
Minassi
Alberto
A
Cascio
Maria Grazia
MG
Allarà
Marco
M
Taglialatela-Scafati
Orazio
O
Pertwee
Roger G
RG
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D050916:TRPV Cation Channels / Q000378:metabolism*
D000577:Amides; D005227:Fatty Acids; D008024:Ligands; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels