Oxyhomologues of anandamide and related endolipids: Chemoselective synthesis and biological activity

Giovanni Appendino*, Alberto Minassi, Luca Berton, Aniello Schiano Moriello, Maria Grazia Cascio, Luciano De Petrocellis, Vincenzo Di Marzo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

The three amide oxyhomologues of the endolipids N-arachidonoylethanolamine (anandamide, AEA, 1a), N-oleoylethanolamine (OEA, 2a), and N- palmitoylethanolamine (PEA, 3a) have been prepared in a chemoselective way, capitalizing on the easy availability of 0-[2-(triisopropylsilyoxy)ethyl] hydroxylamine (6) and the surprising complementary selectivity observed in the acylation of N-[2-(tert-butyldiphenylsilyloxy)-ethyl]hydroxylamine (7) with the PPAA and the DCC/HOBT protocols. Reversal of the cannabinoid CB 1/CB 2 receptor affinity ratio was observed for the first time in a derivative of anandamide (the O-alkyl-N-acyl hydroxylamine 1b), while the other oxyhomologues (1c and 1d) showed only marginal cannabimimetic activity. Compounds with unsaturated acyl chains generally retained vanilloid activity and showed an increased stability toward FAAH compared to their corresponding ethanolamides. Taken together, these observation show that oxyhomologation has a pronounced effect on both the pharmacodynamic and the pharmacokinetic properties of endogenous ethanolamides, suggesting a general relevance of this maneuver for the modification of amide pharmacophores.

Original languageEnglish
Pages (from-to)2333-2338
Number of pages6
JournalJournal of Medicinal Chemistry
Volume49
Issue number7
Early online date22 Feb 2006
DOIs
Publication statusPublished - 1 Apr 2006

Bibliographical note

Acknowledgement:
This research was supported by MIUR (Program:  Chemorecezione Gustativa. Sintesi e Relazioni Attività-Struttura di Molecole Attive sul Sapore). We are grateful to Dr. Paolo Dambruoso for the HMBC measurements.

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