Synthesis and structure-activity relationships of 2-substituted D-tryptophan-containing peptidic endothelin receptor antagonists: importance of the C-2 substituent of the D-tryptophan residue for endothelin A and B receptor subtype selectivity

J Med Chem. 1996 Jun 7;39(12):2313-30. doi: 10.1021/jm9600914.


Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of D-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-D-tryptophans. In contrast, compounds with 2-cyano-D-tryptophan were ETB receptor-selective antagonists. The C-2 substituent of the D-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Drug Design
  • Endothelin Receptor Antagonists*
  • Humans
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Structure-Activity Relationship
  • Substrate Specificity
  • Swine
  • Tryptophan / analogs & derivatives*
  • Tryptophan / pharmacology
  • Vasodilator Agents / chemical synthesis
  • Vasodilator Agents / chemistry
  • Vasodilator Agents / pharmacology*


  • Endothelin Receptor Antagonists
  • Oligopeptides
  • Peptides, Cyclic
  • Piperidines
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Vasodilator Agents
  • BQ 788
  • Tryptophan
  • cyclo(Trp-Asp-Pro-Val-Leu)