TY - JOUR
T1 - Oxyhomologues of anandamide and related endolipids
T2 - Chemoselective synthesis and biological activity
AU - Appendino, Giovanni
AU - Minassi, Alberto
AU - Berton, Luca
AU - Moriello, Aniello Schiano
AU - Cascio, Maria Grazia
AU - De Petrocellis, Luciano
AU - Di Marzo, Vincenzo
N1 - 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.
PY - 2006/4/1
Y1 - 2006/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33645667347&partnerID=8YFLogxK
U2 - 10.1021/jm051240y
DO - 10.1021/jm051240y
M3 - Article
C2 - 16570929
AN - SCOPUS:33645667347
VL - 49
SP - 2333
EP - 2338
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -