Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents

Eur Neuropsychopharmacol. 2008 Oct;18(10):729-50. doi: 10.1016/j.euroneuro.2008.06.002. Epub 2008 Jul 26.

Abstract

This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Binding, Competitive / drug effects*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fear / drug effects
  • Female
  • Fluorobenzenes
  • Gerbillinae
  • Interpersonal Relations
  • Locomotion / drug effects
  • Male
  • Mice
  • Motor Activity / drug effects
  • Neurokinin-1 Receptor Antagonists*
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Wistar
  • Substance P / metabolism
  • Substance P / pharmacology*
  • Vocalization, Animal / drug effects

Substances

  • Fluorobenzenes
  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Substance P
  • Extracellular Signal-Regulated MAP Kinases
  • vestipitant