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

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‐pyridinecarboxamide·2 fumarate), a novel and potent dopamine D 2 , D 3 and 5‐hydroxytryptamine‐3 (5‐HT 3 ) receptors ligand, was investigated in the present study. In guinea‐pig isolated colon, AS‐8112 produced a rightward shift of the concentration‐response curves of 2‐methyl‐5HT, a 5‐HT 3 receptor agonist (pA 2 value of 7.04). Other 5‐HT 3 receptor antagonists also produced such a shift in the following antagonistic‐potency order: granisetron> ondansetron=AS‐8112>>metoclopramide. In mice, AS‐8112 (1.0 – 3.0 mg kg −1 s.c.) potently inhibited hypothermia induced by the dopamine D 3 receptor agonist; R (+)‐7‐OH‐DPAT ( R (+)‐7‐hydroxy‐2‐( N , N ‐di‐ n ‐propylamino)tetraline) (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. In ferrets or dogs, AS‐8112 dose‐dependently inhibited emesis induced by R (+)‐7‐OH‐DPAT, apomorphine, morphine or cisplatin with ID 50 values of 2.22 μg kg −1 s.c., 10.5 μg kg −1 s.c., 14.2 μg kg −1 i.v. and 17.6 μg kg −1 i.v., respectively. Moreover, oral administration of AS‐8112 significantly inhibited emesis induced by these emetogens. AS‐8112 (0.3 mg kg −1 i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS‐8112 is a potent dopamine D 2 , D 3 and 5‐HT 3 receptors antagonist, and a novel anti‐emetic agent with a broad‐spectrum of anti‐emetic activity. These results suggest that this compound is worthy of clinical investigation.British Journal of Pharmacology (2001) 133 , 253–260; doi: 10.1038/sj.bjp.0704078