The enantiomers of zacopride: an intra-species 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 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.
Department of Neuropharmacology, Wyeth Research (U.K.) Ltd, Maidenhead, Berkshire.
D J
DJ
Bill
J
J
Coleman
I
I
Hallett
V C
VC
Middlefell
K F
KF
Rhodes
A
A
Fletcher
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism; D014630:Vagus Nerve / Q000187:drug effects
D014151:Anti-Anxiety Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009467:Neuromuscular Depolarizing Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C055971:zacopride