BMY-33462

The compound BMY 33462 (4‐amino‐N‐(1‐azabicyclo‐[2,2,2]oct‐3‐yl)‐2‐(butan‐2‐one‐3‐yl)oxy‐5‐chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type‐3 (5‐HT3) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5‐HT3 receptor (Ki, 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (Ki > 1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold‐Jarisch reflex in the anesthetized rat (ED50, 0.09 μg/kg, iv), a functional correlate of 5‐HT3 receptor antagonism in vivo. It has been reported that ondansetron and other 5‐HT3 antagonists have the ability to block hyperactivity in rats induced by DiMe‐C7 ([pGlu5, Me‐Phe8, Sar9]SP5–11), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe‐C7‐induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe‐C7‐induced hyperactivity as was haloperiodol and ondansetron. The dopamine‐2 (D2) antagonist haloperidol produced the greatest inhibition of DiMe‐C7‐induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe‐C7‐induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe‐C7‐induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe‐C7‐induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5‐HT3 antagonists to alter a mesolimbic DA‐mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5‐HT3 receptors and 5‐HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5‐HT3 antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side effect liability generally associated with classical neuroleptics. © 1993 Wiley‐Liss, Inc.