title: Central antiemetic effects of AS-8112, a dopamine D2, D3, and 5-HT(3) receptor antagonist, in ferrets.
abstract: The involvement of a central mechanism in the antiemetic effect of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide x 2 fumarate), a novel and potent dopamine D2, D3, and 5-HT(3) receptor antagonist, was investigated in ferrets. Intracerebroventricularly administered AS-8112 dose dependently inhibited R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino) tetraline)-induced emesis (ID(50); 0.11 microg/kg, i.c.v.). In addition, AS-8112 (10 microg/kg, i.c.v.) significantly inhibited emesis induced by cisplatin. Ondansetron (10 microg/kg, i.c.v.) also inhibited cisplatin-induced emesis, but did not inhibit R(+)-7-OH-DPAT-induced emesis. S(-)-eticlopride (10 microg/kg, i.c.v.) did not inhibit emesis induced by cisplatin. However, racemic CP-99,994 ((+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) (10 microg/kg, i.c.v.) inhibited both cisplatin- and R(+)-7-OH-DPAT-induced emesis. These results suggest that the antiemetic effects of AS-8112 are centrally mediated via dopamine D3 and 5-HT(3) receptors in ferrets.
authors.affiliation: Department of Pharmacology I, Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan. takashi-yoshikawa@dainippon-pharm.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Oka
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D002945:Cisplatin; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D005289:Ferrets; D007276:Injections, Intraventricular; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D050637:Receptors, Dopamine D3; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
chemical_list: C431510:5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide 2-fumarate; D000932:Antiemetics; D001381:Azepines; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D011725:Pyridines; D050637:Receptors, Dopamine D3; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D002945:Cisplatin; C031349:7-hydroxy-2-N,N-dipropylaminotetralin