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 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.
Appendino
Giovanni
G
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 9, 28100 Novara, Italy. appendino@pharm.unipmn.it
Minassi
Alberto
A
Berton
Luca
L
Moriello
Aniello Schiano
AS
Cascio
Maria Grazia
MG
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
D000577:Amides; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D063388:Endocannabinoids; D004983:Ethanolamines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D009829:Oleic Acids; D010169:Palmitic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D006898:Hydroxylamines; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C509930:N-arachidonyl-O-(2-hydroxyethyl)hydroxylamine; C494482:TRPV1 protein, human; C033595:N-oleoylethanolamine; C005958:palmidrol; C078814:anandamide