**Background**
Nausea and vomiting are common and distressing side effects associated with various conditions, most notably chemotherapy-induced nausea and vomiting (CINV) resulting from highly emetogenic chemotherapy. The neurokinin 1 (NK1) receptor, which binds substance P, plays a critical role in the emetic reflex and the transmission of signals in the central nervous system. Due to its central involvement in triggering the vomiting response, the NK1 receptor has become a primary therapeutic target for developing long-acting anti-emetic agents. By blocking these receptors, it is possible to attenuate both acute and delayed emesis. In this context, we will introduce a potent and selective NK1 receptor antagonist – Rolapitant.
**Definition**
Rolapitant (SCH619734) is a potent, selective, long-acting, and orally active neurokinin 1 (NK1) receptor antagonist with a Ki value of 0.66 nM for the human NK1 receptor.
**In Vitro and In Vivo Studies**
According to the Rolapitant technical information, this compound exhibits high selectivity, with more than 1000-fold preference for the NK1 subtype over human NK2 and NK3 subtypes. Rolapitant in vitro studies demonstrated that concentrations ranging from 1 to 1000 nM inhibit GR-73632-induced calcium efflux in a concentration-dependent and competitive manner within CHO cells expressing the human NK1 receptor. Furthermore, it shows preferential affinity for NK1 receptors in humans, guinea pigs, gerbils, and monkeys compared to those in rats, mice, and rabbits.
Regarding Rolapitant In Vivo activity, the compound has shown significant efficacy in multiple animal models. In female Mongolian gerbils, Rolapitant (0.03-1 mg/kg PO or 0.3-1 mg/kg IV; single dose) attenuated the GR-73632-induced foot-tapping response dose-dependently, with an ID90 of 0.3 mg/kg for oral administration and complete blockade at 1 mg/kg for intravenous administration. Additionally, in ferret emesis models, Rolapitant (0.03-1 mg/kg PO; single dose) blocked acute emesis induced by both apomorphine (0.125 mg/kg s.c.) and cisplatin (10 mg/kg i.p.). This robust decrease in retches and vomits was maintained throughout a 72-hour observation period. Notably, the Rolapitant description indicates that the compound does not interact with CYP3A4, enhancing its pharmacological profile. In conclusion, Rolapitant is a highly potent and selective NK1 receptor antagonist with significant centrally-mediated anti-emetic effects.
Keywords
Rolapitant, 552292-08-7, SCH619734, SCH 619734, SCH-619734, Neurokinin Receptor, NK receptor, Tachykinin receptor, long-acting, orally active, anti-emetic, emesis, ferret, Mongolian Gerbils, foot tapping, retches, vomits, Inhibitor, inhibitor, inhibit
References
[1] Duffy RA, et al. Rolapitant (SCH 619734): a potent, selective and orally active neurokininNK1 receptor antagonist with centrally-mediated antiemetic effects inferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100.
[2] Rapoport B, et al. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015 Nov;23(11):3281-8.