In vitro and in vivo pharmacological characterization of the novel NK₁ receptor selective antagonist Netupitant

Peptides. 2012 Sep;37(1):86-97. doi: 10.1016/j.peptides.2012.06.010. Epub 2012 Jun 23.


The novel NK(1) receptor ligand Netupitant has been characterized in vitro and in vivo. In calcium mobilization studies CHO cells expressing the human NK receptors responded to a panel of agonists with the expected order of potency. In CHO NK(1) cells Netupitant concentration-dependently antagonized the stimulatory effects of substance P (SP) showing insurmountable antagonism (pK(B) 8.87). In cells expressing NK(2) or NK(3) receptors Netupitant was inactive. In the guinea pig ileum Netupitant concentration-dependently depressed the maximal response to SP (pK(B) 7.85) and, in functional washout experiments, displayed persistent (up to 5h) antagonist effects. In mice the intrathecal injection of SP elicited the typical scratching, biting and licking response that was dose-dependently inhibited by Netupitant given intraperitoneally in the 1-10mg/kg dose range. In gerbils, foot tapping behavior evoked by the intracerebroventricular injection of a NK(1) agonist was dose-dependently counteracted by Netupitant given intraperitoneally (ID(50) 1.5mg/kg) or orally (ID(50) 0.5mg/kg). In time course experiments in gerbils Netupitant displayed long lasting effects. In all the assays Aprepitant elicited similar effects as Netupitant. These results suggest that Netupitant behaves as a brain penetrant, orally active, potent and selective NK(1) antagonist. Thus this molecule can be useful for investigating the NK(1) receptor role in the control of central and peripheral functions. Netupitant has clinical potential in conditions such as chemotherapy induced nausea and vomiting, in which the blockade of NK(1) receptors has been demonstrated valuable for patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Atropine / pharmacology
  • CHO Cells
  • Calcium Signaling
  • Carbachol / pharmacology
  • Cholinergic Agonists / pharmacology
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Female
  • Gerbillinae
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Ileum / drug effects
  • Ileum / metabolism
  • Ileum / physiology
  • In Vitro Techniques
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Male
  • Mice
  • Muscarinic Antagonists / pharmacology
  • Muscle Contraction / drug effects
  • Neurokinin-1 Receptor Antagonists*
  • Nociception / drug effects
  • Protein Binding
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Neurokinin-1 / metabolism
  • Substance P / administration & dosage
  • Substance P / antagonists & inhibitors
  • Substance P / physiology


  • Cholinergic Agonists
  • Muscarinic Antagonists
  • Neurokinin-1 Receptor Antagonists
  • Pyridines
  • Receptors, Neurokinin-1
  • Substance P
  • netupitant
  • Atropine
  • Carbachol