title: A novel opioid structure which accepts protonated as well as non-protonated nitrogen: a family of pure, delta receptor selective antagonists.
abstract: 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).
authors.affiliation: Department of Organic Chemistry, L. Eötvös University, Budapest, Hungary.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Rónai
authors.forename: J
authors.initials: J
authors.lastname: Botyánszki
authors.forename: J
authors.initials: J
authors.lastname: Hepp
authors.forename: K
authors.initials: K
authors.lastname: Medzihradszky
mesh_terms: 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
chemical_list: D004723:Endorphins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011522:Protons; D017465:Receptors, Opioid, delta; D004744:Enkephalin, Methionine; D009584:Nitrogen; C010616:normorphine