Netupitant

Netupitant is a selective neurokinin 1 (NK1) receptor antagonist with potential antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in the prevention of chemotherapy-induced nausea and vomiting (CINV) . (In Vitro) :Netupitant (CID-6451149) binds with high affinity the human NK1 receptor (pKi=9.0) with more than 1000 fold selectivity over the NK2 and NK3 (pKi=5.8 for both sites) .Netupitant (1, 10, 100 nM) concentration-dependently antagonizes the stimulatory effects of substance P (SP) showing insurmountable antagonism (pKB=8.87) in CHO NK1 cells. (In Vivo) :Netupitant (CID-6451149; 1-10 mg/kg; ip) dose-dependently inhibits SP-elicited the typical scratching, biting and licking response in mice. In gerbils, foot tapping behavior evoked by the intracerebroventricular injection of a NK1 agonist is dose-dependently counteracted by Netupitant given intraperitoneally (ID50 1.5mg/kg) or orally (ID50 0.5mg/kg) .Netupitant (0.1-3 mg/kg; i.v.) produces a concentration-dependent inhibition (mean pKB=9.24) of the responses to SP-methylester (SP-OMe) in the detrusor muscle. Netupitant decreases the frequency of reflex bladder contractions.