title: Opioid antagonist properties of the highly delta-receptor-selective BOC-Tyr-Pro-Gly-Phe-Leu-Thr (OtBu) peptide and of its Phe1 and Mel1 analogues.
abstract: BOC-Tyr-Pro-Gly-Phe-Leu-Thr(OtBu) is a potent, highly delta-opioid receptor-selective competitive antagonist, the Ke values in the mouse vas deferens in vitro assay against [D-Ala2, D-Leu5]-enkephalin [D-Pen2, D-Pen5]enkephalin and deltorphin-II being 39.5, 38.7 and 27.3 nM, respectively, whereas those against [D-Ala2, MePhe4-Gly5-ol]enkephalin (DAMGO) and ethylketocyclazocine in the guinea-pig ileum are 368,000 and > 200,000 nM, giving a higher than 9000-fold delta- vs mu- and a higher than 5000-fold delta- vs kappa-selectivity ratio. The Ki values against various labeled delta-ligands in the rat brain receptor binding assay were in the 300-1000 nM range, whereas the Ki against [3H]-DAMGO was higher than 30,000 nM. The striking discrepancies between bioassay and receptor binding data show another aspect of already recognized differences of mouse vas deferens and rat brain delta-receptors. With the aim of producing a delta-selective affinity ligand, we synthesized the BOC-Mel1 derivative; however, there was a 175-fold loss of delta-receptor affinity in the bioassay and no indication of an irreversible interaction, but a delta-agonist effect appeared in spite of nonprotonated nitrogen. The corresponding BOC-Phe1 derivative had a 10 times higher affinity and, apparently, no agonist activity.
authors.affiliation: Research Group of Peptide Chemistry, Hungarian Academy of Sciences, L. Eötvös University, Budapest, Hungary.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Rónai
authors.forename: A
authors.initials: A
authors.lastname: Magyar
authors.forename: G
authors.initials: G
authors.lastname: Orosz
authors.forename: A
authors.initials: A
authors.lastname: Borsodi
authors.forename: S
authors.initials: S
authors.lastname: Benyhe
authors.forename: G
authors.initials: G
authors.lastname: Tóth
authors.forename: E
authors.initials: E
authors.lastname: Makó
authors.forename: E
authors.initials: E
authors.lastname: Kátay
authors.forename: E
authors.initials: E
authors.lastname: Babka
authors.forename: K
authors.initials: K
authors.lastname: Medzihradszky
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000700:Analgesics; D004745:Enkephalins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; C103096:tert-butyloxycarbonyl-tyrosyl-prolyl-glycyl-phenylalanyl-leucyl-(O-tert-butyl)threonine; D016308:Enkephalin, Leucine-2-Alanine; D020881:Enkephalin, D-Penicillamine (2,5)-