Identification of a critical residue in the transmembrane domain 2 of tachykinin neurokinin 3 receptor affecting the dissociation kinetics and antagonism mode of osanetant (SR 142801) and piperidine-based structures

J Med Chem. 2009 Nov 26;52(22):7103-12. doi: 10.1021/jm900948q.

Abstract

In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr139(2.58) in human, corresponding to Ala114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle
  • Cell Line
  • Cell Membrane*
  • Dogs
  • Guinea Pigs
  • Humans
  • Inositol Phosphates / metabolism
  • Isotope Labeling
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Receptors, Neurokinin-3 / chemistry*
  • Receptors, Neurokinin-3 / genetics
  • Receptors, Neurokinin-3 / metabolism
  • Reproducibility of Results
  • Tritium / chemistry

Substances

  • Inositol Phosphates
  • Piperidines
  • Receptors, Neurokinin-3
  • Tritium
  • piperidine
  • SR 142801