Central antiemetic effects of AS-8112, a dopamine D2, D3, and 5-HT(3) receptor antagonist, in ferrets.

摘要

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.