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

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 ay 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] hydroxyl ami ne (7) with the PPAA and the DCC/HOBT protocols. Reversal of the cannabinoid CB1/CB2 receptor affinity ratio was observed for the first time in a derivative of anandamide (the O-alkyl-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 ethanol am ides, suggesting a general relevance of this maneuver for the modification of amide pharmacophores.