Synthesis and in vitro activities of highly potent and selective tripeptide antagonists of the neurokinin NK-1 receptor

Farmaco. 1995 Nov;50(11):755-9.

Abstract

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the tripeptide Ac-Thr-D-Trp(CHO)-Phe-N(Me)-Bzl (1, FR113680) partly modified on the C-terminal amide part. Stereochemistry around the benzilic carbon, as well as nitrogen substitution was investigated. Selected compounds were tested on guinea pig ileum for NK-1, rat colon and rat portal vein for NK-2 and NK-3 receptors, respectively. Two of these peptides were shown to have higher tachykinin antagonist activity (pA2 > 8.8) and selectivity for NK-1 receptors compared with compound 1 taken as reference (Table 2). In addition we investigated the stability of compounds 2 and 3 on guinea pig plasma and liver homogenate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Guinea Pigs
  • Ileum / drug effects
  • In Vitro Techniques
  • Male
  • Molecular Sequence Data
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Neurokinin-1 Receptor Antagonists*
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology
  • Portal Vein / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, Neurokinin-2 / antagonists & inhibitors
  • Receptors, Neurokinin-3 / antagonists & inhibitors

Substances

  • Neurokinin-1 Receptor Antagonists
  • Oligopeptides
  • Receptors, Neurokinin-2
  • Receptors, Neurokinin-3
  • FR 113680