A novel opioid structure which accepts protonated as well as non-protonated nitrogen: a family of pure, delta receptor selective antagonists.
Conventional opioids including opioid peptides require an "opioid" nitrogen which exists in protonated state while interacting with the receptor. In the present paper we demonstrate that the Tyr-Pro-Gly-Phe-Leu-Thr hexapeptide sequence accepts N-terminal substituents such as N-t-Boc, N-phenylacetyl and N-diphenylacetyl where the N cannot become protonated, as well as "traditional" substitutions such as N,N-diallyl, where protonation is likely under physiological conditions. The opioid peptides bearing these substituents are pure antagonists of medium affinity (Ke values in the mouse vas deferens bioassay against [Met5]-enkephalin are in the 3 x 10(-7)-4 x 10(-6) M range) with a high delta receptor preference (50-350-fold delta over mu selectivity ratios).
Rónai
A Z
AZ
Department of Organic Chemistry, L. Eötvös University, Budapest, Hungary.
Botyánszki
J
J
Hepp
J
J
Medzihradszky
K
K
D000595:Amino Acid Sequence; D000818:Animals; D004723:Endorphins / Q000737:chemistry* / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009022:Morphine Derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists; D009584:Nitrogen / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D011522:Protons; D017465:Receptors, Opioid, delta; D014649:Vas Deferens / Q000187:drug effects
D004723:Endorphins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011522:Protons; D017465:Receptors, Opioid, delta; D004744:Enkephalin, Methionine; D009584:Nitrogen; C010616:normorphine