Studies on Neurokinin Antagonists. 1. The Design of Novel Tripeptides Possessing the glutaminyl-D-tryptophylphenylalanine Sequence as Substance P Antagonists

J Med Chem. 1992 May 29;35(11):2015-25. doi: 10.1021/jm00089a011.

Abstract

To discover a novel and low molecular weight substance P (SP) antagonist we postulated that the essential binding domain of peptide ligands was only a small portion in the whole structure. On the basis of this assumption, we selected the known octapeptide SP antagonist D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Phe-NH2 (1) as a lead and synthesized its fragment tripeptides which were evaluated for their activity to block 3H-SP binding on guinea pig lung membranes. The protected tripeptide N alpha-[N alpha-[N alpha-(tert-butyloxycarbonyl)-L-glutaminyl]-N1-formyl-D-tryptophyl]- L-phenylalanine benzyl ester [Boc-Gln-D-Trp(CHO)-Phe-OBzl (4a)], corresponding to the Gln-D-Trp-Phe part of 1, exhibited 7-fold potent inhibitory activity in comparison with 1. Studies on structure-activity relationships revealed that the D-tryptophan, L-phenylalanine, and benzyl ester were quite important to maintain the high binding affinity. It was also indicated that 4a antagonized the SP-induced contraction of isolated guinea pig trachea strips (IC50 = 4.7 x 10(-6) M).

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Guinea Pigs
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Molecular Sequence Data
  • Muscle Contraction / drug effects
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Structure-Activity Relationship
  • Substance P / antagonists & inhibitors*
  • Substance P / metabolism
  • Substance P / pharmacology
  • Trachea / drug effects
  • Trachea / physiology

Substances

  • Oligopeptides
  • Peptide Fragments
  • N(alpha)-(N(alpha)-(N(alpha)-(tert-butyloxycarbonyl)glutaminyl)-N(1)-formyl-tryptophyl)phenylalanine benzyl ester
  • Substance P