Conformationally Constrained Fatty Acid Ethanolamides as Cannabinoid and Vanilloid Receptor Probes

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• 作者：Giovanni Appendino ; Alessia Ligresti ; Alberto Minassi ; Maria Grazia Cascio ; Marco Allar ; Orazio Taglialatela-Scafati ; Roger G. Pertwee ; Luciano De Petrocellis ; Vincenzo Di Marzo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：3001-3009
• 全文大小：200K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

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.