AbstractIn the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA2= 9.8) antagonist at 5‐hydroxytryptamine3(5‐HT3) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold‐Jarisch reflex elicited by iv injection of 5‐HT; the iv ED50was approximately 3 μg/kg and following a dose of 140 μg/kg iv the reflex was abolished for>85 min. The compound displayed no significant affinity for 5‐HT1, 5‐HT2, or a variety of other radioligand binding sites at concentration of 10 μM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti‐cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05–0.5 mg/kg) administered 30 min before and 45 min prior to cisplatin, were clearly anti‐emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin were also effective. Minimal changes in the behaviour of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron is a potent, selective, and reversible antagonist at neuronal 5‐HT3receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting