Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists

J Med Chem. 2001 May 24;44(11):1675-89. doi: 10.1021/jm000501v.


A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human mu-opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant micro-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry
  • Morpholines / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Radioligand Assay
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Receptors, Neurokinin-2 / chemistry
  • Receptors, Neurokinin-2 / metabolism
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Receptors, Neurokinin-3 / chemistry
  • Receptors, Neurokinin-3 / metabolism
  • Receptors, Opioid, mu / chemistry
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship


  • Morpholines
  • Piperidines
  • Quinolines
  • Receptors, Neurokinin-2
  • Receptors, Neurokinin-3
  • Receptors, Opioid, mu
  • SB 400238
  • SB 414240