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

Abstract 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 (p K 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 (p K B 7.85) and, in functional washout experiments, displayed persistent (up to 5 h) 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 1–10 mg/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 1.5 mg/kg) or orally (ID 50 0.5 mg/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.