Pharmacological properties of dolasetron, a potent and selective antagonist at 5‐HT 3 receptors

In the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA 2 = 9.8) antagonist at 5‐hydroxytryptamine 3 (5‐HT 3 ) 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 ED 50 was 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‐HT 1 , 5‐HT 2 , 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‐HT 3 receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting. © 1993 Wiley‐Liss, Inc.