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Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template.

Authors
  • Sisto, A
  • Bonelli, F
  • Centini, F
  • Fincham, C I
  • Potier, E
  • Monteagudo, E
  • Lombardi, P
  • Arcamone, F
  • Goso, C
  • Manzini, S
Type
Published Article
Journal
Biopolymers
Publication Date
Oct 01, 1995
Volume
36
Issue
4
Pages
511–524
Identifiers
PMID: 7578945
Source
Medline
License
Unknown

Abstract

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.

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