Neurokinin (NK) receptors belong to the family of G-protein coupled receptors and can be divided into three subtypes: NK1, NK2 and NK3. The endogenous ligand for NK1 receptor is the 11 amino acid neuropeptide substance P (SP)[3]. Netupitant is a highly potent and selective, orally active neurokinin-1 receptor antagonist with Ki of 0.95 nM[3]. In CHO NK1 cells, netupitant concentration-dependently antagonized the stimulatory effects of substance P (SP) showing insurmountable antagonism (pK(B) 8.87)[4]. 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 1-10 mg/kg dose range. In gerbils, foot tapping behavior evoked by the intracerebroventricular injection of a NK1 agonist was dose-dependently counteracted by netupitant given intraperitoneally (ID(50) 1.5mg/kg) or orally (ID(50) 0.5mg/kg)[4].
Netupitant/奈妥吡坦 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Guinea-pig isolated detrusor muscle
Guinea-pig isolated detrusor muscle
To evaluate the inhibitory effect of Netupitant on SP-OMe-induced contractions. Netupitant concentration-dependently inhibited SP-OMe-induced contractions, with 3 and 10 nM producing parallel rightward shifts and 30 nM completely suppressing contractions.
Front Pharmacol. 2016 Aug 4;7:234.
Netupitant/奈妥吡坦 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Knockin mice expressing human NK1R
Intrathecally
100 nM/5 µL
Single injection, lasting 8 hours
Evaluate the inhibitory effect of NK1R antagonists on capsaicin-induced mechanical allodynia
Proc Natl Acad Sci U S A. 2023 May 30;120(22):e2220979120.
Guinea-pigs
Isovolumetric bladder contractions model and acetic acid-induced bladder overactivity model
Intravenous injection
0.1–3 mg/kg
Single administration
To evaluate the effect of Netupitant on bladder contraction frequency and amplitude. Netupitant dose-dependently reduced bladder contraction frequency without altering contraction amplitude.
Front Pharmacol. 2016 Aug 4;7:234.
Ferrets and Suncus murinus
Chemotherapy-induced emesis model
Oral
0.03–3 mg/kg
Single administration
Netupitant significantly reduced cisplatin-induced acute and delayed emesis and showed superior anti-emetic effects when combined with other drugs
Front Pharmacol. 2016 Aug 31;7:263
Suncus murinus (House Musk Shrew)
Cisplatin- and motion-induced emesis model
Oral
1 mg/kg
Single dose, observed for 24 hours
To evaluate the anti-emetic effects of Netupitant alone or in combination with Palonosetron and HM01 against cisplatin-induced emesis. Netupitant alone reduced cisplatin-induced emesis by approximately 40%, and the effect was enhanced when combined with Palonosetron.
Front Pharmacol. 2018 Aug 6;9:869
Least shrew
Emesis model
Intraperitoneal injection
10 mg/kg
Single administration, emetic responses were recorded for 30 min
To evaluate the antiemetic effect of Netupitant on MK-2206-induced vomiting, results showed complete suppression at 10 mg/kg dose
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