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

David J. Bill

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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James Coleman,

James Coleman

Molecular Pharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Ian Hallett,

Ian Hallett

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Vicki C. Middlefell,

Vicki C. Middlefell

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Keith F. Rhodes,

Keith F. Rhodes

Molecular Pharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Allan Fletcher,

Corresponding Author

Allan Fletcher

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PHSearch for more papers by this author

David J. Bill,

David J. Bill

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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James Coleman,

James Coleman

Molecular Pharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Ian Hallett,

Ian Hallett

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Vicki C. Middlefell,

Vicki C. Middlefell

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Keith F. Rhodes,

Keith F. Rhodes

Molecular Pharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

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Allan Fletcher,

Corresponding Author

Allan Fletcher

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PH

Departments of Neuropharmacology, Wyeth Research (U.K.) Ltd, Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 0PHSearch for more papers by this author

First published: July 1995

https://doi.org/10.1111/j.1476-5381.1995.tb15000.x

Citations: 4

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Abstract

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 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-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 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%; MED₈₅) 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-HT₃ 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.

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Volume115, Issue5

July 1995

Pages 775-780

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

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

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