PHARMACOLOGICAL PROPERTIES OF DOLASETRON, A POTENT AND SELECTIVE ANTAGONIST AT 5-HT3 RECEPTORS

In the rabbit isolated perfused heart, dolasetron (MDL 73,147) was found to be a potent (pA2 = 9.8) antagonist at 5-hydroxytryptamine, (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 ED50 was approximately 3 mug/kg and following a dose of 140 mug/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 a concentration of 10 muM. 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 after 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 behavior 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-HT3 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.