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

D J Bill, J Coleman, I Hallett, V C Middlefell, K F Rhodes, A Fletcher

Department of Neuropharmacology, Wyeth Research (U.K.) Ltd, Maidenhead, Berkshire.

British journal of pharmacology 1995 Jul

filter terms:

1. The 5-HT3 receptor antagonist, zacopride, and its enantiomers, R(+)-zacopride and S(-)-zacopride, were examined in three pharmacological models: (i) 5-HT-induced depolarization 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-HT3 receptor antagonists were also included for comparison in these studies. 2. Racemic zacopride, and both of the enantiomers, displayed potent 5-HT3 receptor antagonist activity in the isolated vagus nerve and in the von Bezold-Jarisch model. No 5-HT3 receptor agonist or partial agonist effects of these compounds were detected. 3. In the isolated vagus nerve, R(+)-zacopride and ondansetron were surmountable 5-HT3 receptor antagonists (pA2 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 WAY100289 were potent antagonists of the 5-HT-evoked von Bezold-Jarisch reflex, with minimum effective doses (lowest dose required to reduce the reflex by > or = 85%; MED85) of 1.0, 3.0, 0.3 and 3.0 micrograms 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 microgram kg-1, s.c.) and similar active dose-ranges (1-1000 micrograms kg-1, s.c.). 6. The doses of racemic zacopride, R( + )-zacopride and S(-)-zacopride required to block 5-HT3receptors 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 ofR( + )-zacopride and S(-)-zacopride.

Citation

D J Bill, J Coleman, I Hallett, V C Middlefell, K F Rhodes, A Fletcher. The enantiomers of zacopride: an intra-species comparison of their potencies in functional and anxiolytic models. British journal of pharmacology. 1995 Jul;115(5):775-80