THE ENANTIOMERS OF ZACOPRIDE - AN INTRASPECIES COMPARISON OF THEIR POTENCIES IN FUNCTIONAL AND ANXIOLYTIC MODELS

1 The 5-HT3 receptor antagonist, zacopride, and its enantiomers, R(+)- zacopride and S(-)-zacopride, were examined in three pharmacological m odels: (i) 5-HT-induced depolarization of the mouse isolated. vagus ne rve preparation, (ii) the 5-HT-evoked von Bezold-Jarisch reflex in the mouse, apd (iii) the mouse light:dark box model of anxiety. Other sta ndard 5-HT3 receptor antagonists were also included for comparison in these studies. 2 Racemic zacopride, and both of the enantiomers, displ ayed potent 5-HT3 receptor antagonist activity in the isolated vagus n erve and in the von Bezold-Jarisch model. No 5-HT3 receptor agonist or partial agonist effects of these compounds were detected. 3 In the is olated vagus nerve, R(+)-zacopride and ondansetron were surmountable 5 -HT3 receptor antagonists (pA(2) values of 9.3 and 8.3, respectively), whereas racemic zacopride, S(-)-zacopride and tropisetron were insurm ountable antagonists, markedly i 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-Jarisc h reflex, with minimum effective doses(!lowest dose required to reduce the reflex by greater than or equal to 85%; MED(85)) Of 1.0, 3.0; 0.3 and 3.0 mu g kg(-1), s.c., respectively. 5 Racemic zacopride, R(+)-za copride and S(-)-zacopride were active in the mouse light:dark box mod el of anxiety, with similar potencies (minimum effective dose 1 mu g k g(-1), s.c.) and similar active dose-ranges (1-1000 mu g kg(-1), s.c.) . 6 The doses of racemic zacopride, R(+)-zacopride and S(-)-zacopride required to block 5-HT3 receptors in vivo correlated reasonably well w ith their potencies in an anxiety model within the same species. In th ese studies, there was no evidence of a marked difference between the anxiolytic potencies of R(+)-zacopride and S(-)-zacopride.