Design and synthesis of new linear and cyclic bradykinin antagonists

J Med Chem. 1996 May 10;39(10):2095-101. doi: 10.1021/jm950682e.


We report here on the synthesis and pharmacological properties of a new series of small linear and cyclic peptides derived from the five C-terminal amino acid residues of second-generation bradykinin receptor antagonists. Variations of the two first residues of the pentapeptide (Thi-Ser-D-Tic-Oic-Arg) were shown to modulate the biological activities of the analogs on bradykinin-induced smooth muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific of the B2 bradykinin receptor. Several analogs showed pA2 values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg-], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA2 of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 receptor. The pKB values obtained for these compounds on these tissue preparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA2 < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II' beta-turn structure. This analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bradykinin Receptor Antagonists*
  • Drug Design*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Sequence Data
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Rabbits


  • Bradykinin Receptor Antagonists
  • Peptides, Cyclic