New reduced peptide bond substance P agonists and antagonists: effects on smooth muscle contraction

Susan Zacharia, Wojciech J. Rossowski, Jiang Ning-Yi, Pavel Hrbas, Atilla Ertan, David H. Coy

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Following the recent discovery of a new substance P (SP) competitive pancreatic acini cell receptor antagonist containing a reduced peptide bond in place of the C-terminal peptide bond, a new series of full chain and short chain (heptapeptide and hexapeptide) substance P analogues have been prepared in which one of the C-terminal-region peptide bonds has been replaced by CH2NH or CH2O groups. They were compared for their ability to recognize NK1 and/or NK2 tachykinin receptor binding sites on guinea pig ileum and rat duodenum smooth muscle preparations, respectively. It was found that all full sequence SP pseudopeptides were agonists with much reduced bioactivity in both tested systems and, in addition, [Gly9 ψ CH2NH)Leu10,Leu11]SP was found to be a relatively selective agonist for NK1 binding sites. Substitution of leucine at position 11 of SP heptapseudopeptides with phenylalanine generated a pseudopeptide with weak agonist activity when Gln at position 5 was replaced by D-Phe, or antagonists when this residue was replaced by D-Nal or D-Cpa. [Leu9ψ(CH2NH)Leu11]SP-(6-11) with Gln at position 6 substituted by D-Phe was a relatively stronger antagonist in both assay systems. These results suggest that, as with several other peptide systems of late, manipulation of the peptide bonds in SP can produce receptor antagonists which in some cases approach the potency of the classic spantide series and, furthermore, that the approach might be used to induce NK receptor specificity in both agonist and antagonist analogs.

Original languageEnglish (US)
Pages (from-to)353-357
Number of pages5
JournalEuropean Journal of Pharmacology
Issue number3
StatePublished - Oct 22 1991


  • Duodenum (rat)
  • Ileum (guinea-pig)
  • NK receptors
  • NK receptors
  • Spantide
  • Substance P
  • Substance P analogues (hepta- and hexapseudopeptide)

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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