Monocyclic human tachykinin NK-2 receptor antagonists as evolution of a potent bicyclic antagonist: QSAR and site-directed mutagenesis studies

J Med Chem. 2002 Aug 1;45(16):3418-29. doi: 10.1021/jm011127h.


A new series of monocyclic pseudopeptidic tachykinin NK-2 receptor antagonists has been derived from nepadutant with the help of site-directed mutagenesis studies and QSAR models. MEN11558 is the lead compound which is evaluated on a series of 13 new human tachykinin NK-2 receptor mutants (Tyr107Ala, Gln109Ala, Asn110Ala, Phe112Ala, Ser164Phe, Cys167Gly, Phe168Ala, Tyr169Ala, Ile202Phe, Trp263Ala, Tyr269Phe, Tyr269Ala, and Phe293Ala) and 8 mutants on which data from nepadutant were already available (Gln166Ala, Ser170Ala, Thr171Ala, His198Ala, Tyr206Phe, Tyr266Phe, Tyr289Phe, and Tyr289Thr). The results show that the two compounds share most of their binding sites, in agreement with their hypothesized binding modes. This allows us to transfer the structural knowledge we already had for nepadutant to the new series of compounds. At the same time, a sound QSAR model is developed to assist the prioritization of new chemical syntheses. The result is the discovery of receptor antagonists with a higher affinity than nepadutant for the hNK-2 receptor.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Binding, Competitive
  • Humans
  • In Vitro Techniques
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Mimicry
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Receptors, Neurokinin-2 / chemistry*
  • Receptors, Neurokinin-2 / metabolism
  • Tachykinins / metabolism*


  • Ligands
  • MEN 11420
  • MEN 11558
  • Peptides, Cyclic
  • Receptors, Neurokinin-2
  • Tachykinins