Novel deltorphin heptapeptide analogs with potent delta agonist, delta antagonist, or mixed mu antagonist/delta agonist properties.
A series of deltorphin (DLT: Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) analogs in which Leu5 and/or Met6 were mainly replaced by t-Leu(Tle) and/or N alpha-alkylated glycine were synthesized and examined for their receptor binding properties and in vitro bioactivities by guinea pig ileum (GPI) and mouse vas deferens (MVD) assays. [Tle5]DLT(2) showed a dramatic decrease in the MVD potency when compared to the parent peptide and was found to have a potent delta receptor antagonist activity against various delta agonists with Ke values of 16-311 nM. Interestingly, the antagonist potency of 2 against DPDPE as agonist was 20-fold weaker than that against deltorphins or Leu-enkephalin. Among the analogs in which Met6 was replaced by an N alpha-alkylated Gly residue, [N alpha-isobutyl-Gly6]DLT(5) behaved as a mixed mu antagonist/delta agonist while its isomeric analogs in which the N alpha-alkyl is n-butyl (4) or (R or S) sec-butyl (6a,b) were very potent delta receptor agonists. Analogs 2, 4, 6a, and 6b were highly stable against rat brain and rat plasma enzymes and thus may represent a starting point for the development of novel receptor-specific compounds useful as ligands for studies of opioid receptors.
Sasaki
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Y
Department of Biochemistry, Tohoku College of Pharmacy, Sendai, Japan.
Chiba
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T
D000595:Amino Acid Sequence; D000818:Animals; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004745:Enkephalins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin; D020881:Enkephalin, D-Penicillamine (2,5)-