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 language | English |
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Pages (from-to) | 3001-3009 |
Number of pages | 9 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 9 |
Early online date | 10 Apr 2009 |
DOIs | |
Publication status | Published - 14 May 2009 |
Keywords
- sensory neurons
- TRPV1 channels
- VR1 receptor
- anandamide
- CB1
- brain
- arvanil
- ligand
- lipoxygenases
- antagonist