title: Anti-emetic activity of the novel nonpeptide tachykinin NK1 receptor antagonist ezlopitant (CJ-11,974) against acute and delayed cisplatin-induced emesis in the ferret.
abstract: The anti-emetic effects of a novel tachykinin NK(1) receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N-[(2-methoxy, 5-isopropylphenyl)methyl]-1-azabicyclo- [2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [(3)H]substance P ([(3)H]SP) binding to the human, guinea pig, ferret and gerbil NK(1) receptors (K(i) = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to NK(2) and NK(3) receptors up to 1 micromol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA(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(9),Met(O(2))(11)]SP in gerbils, which is known to be mediated by NK(1) receptors in the brain. These findings indicate that ezlopitant is a potent and selective NK(1) receptor antagonist, and that it inhibits both acute and delayed emetic reactions induced by cisplatin in ferrets via acting on NK(1) receptors in the central nervous system.
authors.affiliation: Pfizer Global Research and Development, Nagoya Laboratories, Takeyoto, Japan. Tsuchiya@japan.pfizer.com
authors.forename: Megumi
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kanai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mizutani
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimada
authors.forename: Osamu
authors.initials: O
authors.lastname: Suga
authors.forename: Satoko
authors.initials: S
authors.lastname: Ueda
authors.forename: John W
authors.initials: JW
authors.lastname: Watson
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagahisa
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D005289:Ferrets; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D011485:Protein Binding / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D014839:Vomiting / Q000139:chemically induced* / Q000188:drug therapy*
chemical_list: D000932:Antiemetics; D001596:Benzylamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; C413864:ezlopitant; D002945:Cisplatin