Anti-Emetic Activity of the Novel Nonpeptide Tachykinin NK[sub 1] Receptor Antagonist Ezlopitant (CJ-11,974) against Acute and Delayed Cisplatin-Induced Emesis in the Ferret.

The anti-emetic effects of a novel tachykinin NK[sub 1] receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N--1-azabicyclo- [2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [[sup 3] H]substance P ([[sup 3] H]SP) binding to the human, guinea pig, ferret and gerbil NK[sub 1] receptors (K[sub i] = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to NK[sub 2] and NK[sub 3] receptors up to 1 μmol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA[sub 2] value of 7.8, but had no effects on the baseline tension and maximum contractile response. In ferrets, ezlopitant, either orally (0.03–3 mg/kg) or subcutaneously (0.3–3 mg/kg), prevented acute retching and vomiting responses induced by intraperitoneal injection of cisplatin (10 mg/kg). In addition, repeated subcutaneous injection of ezlopitant significantly inhibited delayed retching and vomiting responses that occurred in ferrets treated with the lower dose of cisplatin (5 mg/kg, i.p.). Ezlopitant (0.1–1 mg/kg, s.c.) also produced a dose-dependent inhibition of hindpaw tapping induced by intracerebroventricular injection of [Sar[sup 9] ,Met(O[sub 2] )[sup 11] ]SP in gerbils, which is known to be mediated by NK[sub 1] receptors in the brain. These findings indicate that ezlopitant is a potent and selective NK[sub 1] receptor antagonist, and that it inhibits both acute and delayed emetic reactions induced by cisplatin in ferrets via acting on NK[sub 1] receptors in the central nervous system.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]