The enantiomers of zacopride: an intra‐species comparison of their potencies in functional and anxiolytic models

1 The 5‐HT 3 receptor antagonist, zacopride, and its enantiomers, R(+)‐zacopride and S(−)−zacopride, were examined in three pharmacological models: (i) 5‐HT‐induced depolarizarion of the mouse isolated vagus nerve preparation, (ii) the 5‐HT‐evoked von Bezold‐Jarisch reflex in the mouse, and (iii) the mouse light:dark box model of anxiety. Other standard 5‐HT 3 receptor antagonists were also included for comparison in these studies. 2 Racemic zacopride, and both of the enantiomers, displayed potent 5‐HT 3 receptor antagonist activity in the isolated vagus nerve and in the von Bezold‐Jarisch model. No 5‐HT 3 receptor agonist or partial agonist effects of these compounds were detected. 3 In the isolated vagus nerve, R (+)‐zacopride and ondansetron were surmountable 5‐HT 3 receptor antagonists (pA 2 values of 9.3 and 8.3, respectively), whereas racemic zacopride, S(—)‐zacopride and tropisetron were insurmountable antagonists, markedly suppressing the maximum response to 5‐HT. 4 In vivo , racemic zacopride, R (+)‐zacopride, S(—)‐zacopride and WAY 100289 were potent antagonists of the 5‐HT‐evoked von Bezold‐Jarisch reflex, with minimum effective doses (lowest dose required to reduce the reflex by ≥85%; MED 85 ) of 1.0, 3.0, 0.3 and 3.0 μg kg −1 , s.c, respectively. 5 Racemic zacopride, R (+)‐zacopride and S(—)‐zacopride were active in the mouse light:dark box model of anxiety, with similar potencies (minimum effective dose 1 μg kg −1 , s.c.) and similar active dose‐ranges (1–1000 μg kg −1 , s.c). 6 The doses of racemic zacopride, R (+)‐zacopride and S(−)−zacopride required to block 5‐HT 3 receptors in vivo correlated reasonably well with their potencies in an anxiety model within the same species. In these studies, there was no evidence of a marked difference between the anxiolytic potencies of R (+)‐zacopride and S(—)‐zacopride.