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

J Med Chem. 2006 Apr 6;49(7):2333-8. doi: 10.1021/jm051240y.


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 O-[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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides
  • Amidohydrolases / metabolism
  • Animals
  • Arachidonic Acids / chemical synthesis*
  • Arachidonic Acids / metabolism
  • Arachidonic Acids / pharmacology
  • Cell Line
  • Chlorocebus aethiops
  • Endocannabinoids
  • Ethanolamines / chemical synthesis*
  • Ethanolamines / pharmacology
  • Humans
  • Hydrolysis
  • Hydroxylamines / chemical synthesis*
  • Hydroxylamines / pharmacology
  • Oleic Acids
  • Palmitic Acids / chemical synthesis*
  • Palmitic Acids / pharmacology
  • Polyunsaturated Alkamides
  • Rats
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism
  • Structure-Activity Relationship
  • TRPV Cation Channels / metabolism


  • Amides
  • Arachidonic Acids
  • Endocannabinoids
  • Ethanolamines
  • Hydroxylamines
  • N-arachidonyl-O-(2-hydroxyethyl)hydroxylamine
  • Oleic Acids
  • Palmitic Acids
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • TRPV Cation Channels
  • TRPV1 protein, human
  • N-oleoylethanolamine
  • palmidrol
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide