Rational design of high affinity tachykinin NK2 receptor antagonists

Bioorg Med Chem. 1994 Feb;2(2):101-13. doi: 10.1016/s0968-0896(00)82006-4.


The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Colon / drug effects
  • Cricetinae
  • Drug Design
  • In Vitro Techniques
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Peptoids
  • Protein Conformation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urinary Bladder / drug effects


  • Oligopeptides
  • Peptoids
  • Receptors, Neurokinin-2