THE DIFFERENTIAL ACTIVITIES OF R(+)-ZACOPRIDE AND S(-)-ZACOPRIDE AS 5-HT3 RECEPTOR ANTAGONISTS

R(+)- and S(-)-zacropride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [H-3]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [H-3]S(-)-zacopride and [H-3]R(+)-zacopride labelled homogeneous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride competed for a further 10 to 20% of the binding of [H-3]R(+)/S(-)-zacopride or [H-3]R(+)-zacopride in excess of that competed for by S(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.