Central antiemetic effects of AS-8112, a dopamine D2, D3, and 5-HT3 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-1 H -1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide·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 μg/kg, i.c.v.). In addition, AS-8112 (10 μg/kg, i.c.v.) significantly inhibited emesis induced by cisplatin. Ondansetron (10 μg/kg, i.c.v.) also inhibited cisplatin-induced emesis, but did not inhibit R (+)-7-OH-DPAT-induced emesis. S (−)-eticlopride (10 μg/kg, i.c.v.) did not inhibit emesis induced by cisplatin. However, racemic CP-99,994 ((±)-(2 S , 3 S )-3-(2-methoxybenzylamino)-2-phenylpiperidine) (10 μg/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.