The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D-2, D-3 and 5-HT3 receptors antagonist

1 The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1- ethyl-4-methylhexahydro-1-H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-py ridinecarboxamide .2 fumarate), a novel and potent dopamine D-2, D-3 and 5- hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the prese nt study. 2 In guinea-pig isolated colon, AS-8112 produced a rightward shift of the c oncentration-response curves of 2-methyl-SHT, a 5-HT3 receptor agonist (pA( 2) value of 7.04). Other 5-HT3 receptor antagonists also produced such a sh ift in the following antagonistic-potency order: granisetron > ondansetron = AS-8112 > metoclopramide. 3 In mice, AS-8112 (1.0-3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy -2-(N,N-di-n-propylamino)tetra-line) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol. which have affinity for dopamine D-3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. 4 In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 mug kg(-1) s.c., 10.5 mug kg(-1) s.c., 14.2 mug kg(-1) i.v. and 17.6 mug k g(-1) i.v., respectively. Moreover, oral administration of AS-8112 signific antly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i .v.) significantly inhibited emesis induced by cyclophosphamide and doxorub icin. 5 In conclusion, AS-8112 is a potent dopamine D-2, D-3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-eme tic activity. These results suggest that this compound is worthy of clinica l investigation.