Neurokinin 1 receptor antagonists: correlation between in vitro receptor interaction and in vivo efficacy

J Pharmacol Exp Ther. 2007 Sep;322(3):1286-93. doi: 10.1124/jpet.107.124958. Epub 2007 Jun 15.


We compared the neurokinin 1 receptor (NK(1)R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca(2+) mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK(1)R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK(1)R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 micromol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 micromol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 micromol/kg) inhibited GFT and occupied striatal NK(1)R by 100% for >48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK(1)R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium Signaling
  • Cell Line
  • Gerbillinae
  • Humans
  • Neurokinin-1 Receptor Antagonists*
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Sulfoxides / administration & dosage
  • Sulfoxides / pharmacokinetics*
  • Sulfoxides / pharmacology


  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Sulfoxides
  • ZD 6021
  • 3-(2-methoxybenzylamino)-2-phenylpiperidine