Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists

J Med Chem. 1996 Apr 12;39(8):1664-75. doi: 10.1021/jm950892r.


The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)alphaMePheNH(CH2)7NHCONH2 (41, PD157672). This modified dipeptide has a Ke of 7 nM in blocking senktide-induced increases in intracellular calcium levels in human NK3 receptors stably expressed in CHO cells. Subsequent optimization of the N-terminal BocPhe group and the alphaMePhe residue side chain of 41 led to the identification of [S-(R*,S*)]-[2-(2,3-difluorophenyl)-1-methyl-1-[(7-ureidoheptyl)ca r bamoyl]ethyl]carbamic acid 2-methyl-1-phenylpropyl ester (60, PD161182), a non-peptide NK3 receptor selective antagonist. Compound 60 blocks the senktide-evoked increases in intracellular calcium levels in cloned human NK3 receptors stably expressed in CHO cells with Ke of 0.9 nM.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • Dipeptides / pharmacology*
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Molecular Sequence Data
  • Peptoids
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Receptors, Neurokinin-3 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship


  • Dipeptides
  • Peptoids
  • Receptors, Neurokinin-3