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. 1995 Jul;115(5):775–780. doi: 10.1111/j.1476-5381.1995.tb15000.x

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

D J Bill 1, J Coleman 1, I Hallett 1, V C Middlefell 1, K F Rhodes 1, A Fletcher 1
PMCID: PMC1908521  PMID: 8548176

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 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.).(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Andrews P. L., Rapeport W. G., Sanger G. J. Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci. 1988 Sep;9(9):334–341. doi: 10.1016/0165-6147(88)90106-x. [DOI] [PubMed] [Google Scholar]
  2. Barnes J. M., Barnes N. M., Costall B., Domeney A. M., Johnson D. N., Kelly M. E., Munson H. R., Naylor R. J., Young R. The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists. Pharmacol Biochem Behav. 1990 Dec;37(4):717–727. doi: 10.1016/0091-3057(90)90554-u. [DOI] [PubMed] [Google Scholar]
  3. Barnes N. M., Costall B., Ge J., Kelly M. E., Naylor R. J. The interaction of R(+)- and S(-)-zacopride with PCPA to modify rodent aversive behaviour. Eur J Pharmacol. 1992 Jul 21;218(1):15–25. doi: 10.1016/0014-2999(92)90142-q. [DOI] [PubMed] [Google Scholar]
  4. Bill D. J., Fletcher A., Glenn B. D., Knight M. Behavioural studies on WAY100289, a novel 5-HT3 receptor antagonist, in two animal models of anxiety. Eur J Pharmacol. 1992 Aug 6;218(2-3):327–334. doi: 10.1016/0014-2999(92)90186-8. [DOI] [PubMed] [Google Scholar]
  5. Bradley G., Ward T. J., White J. C., Coleman J., Taylor A., Rhodes K. F. Novel antagonists of the 5-HT3 receptor. Synthesis and structure-activity relationships of (2-alkoxybenzoyl)ureas. J Med Chem. 1992 May 1;35(9):1515–1520. doi: 10.1021/jm00087a003. [DOI] [PubMed] [Google Scholar]
  6. Costall B., Domeney A. M., Gerrard P. A., Kelly M. E., Naylor R. J. Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol. 1988 Apr;40(4):302–305. doi: 10.1111/j.2042-7158.1988.tb05254.x. [DOI] [PubMed] [Google Scholar]
  7. Costall B., Naylor R. J., Tyers M. B. The psychopharmacology of 5-HT3 receptors. Pharmacol Ther. 1990;47(2):181–202. doi: 10.1016/0163-7258(90)90086-h. [DOI] [PubMed] [Google Scholar]
  8. Crawley J. N. Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol Biochem Behav. 1981 Nov;15(5):695–699. doi: 10.1016/0091-3057(81)90007-1. [DOI] [PubMed] [Google Scholar]
  9. File S. E., Andrews N. Enhanced anxiolytic effect of zacopride enantiomers in diazepam-withdrawn rats. Eur J Pharmacol. 1993 Jun 11;237(1):127–130. doi: 10.1016/0014-2999(93)90101-m. [DOI] [PubMed] [Google Scholar]
  10. Fozard J. R. MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1984 May;326(1):36–44. doi: 10.1007/BF00518776. [DOI] [PubMed] [Google Scholar]
  11. Ireland S. J., Tyers M. B. Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. Br J Pharmacol. 1987 Jan;90(1):229–238. doi: 10.1111/j.1476-5381.1987.tb16844.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kilpatrick G. J., Bunce K. T., Tyers M. B. 5-HT3 receptors. Med Res Rev. 1990 Oct-Dec;10(4):441–475. doi: 10.1002/med.2610100404. [DOI] [PubMed] [Google Scholar]
  13. Middlefell V. C., Price T. L. 5-HT3 receptor agonism may be responsible for the emetic effects of zacopride in the ferret. Br J Pharmacol. 1991 May;103(1):1011–1012. doi: 10.1111/j.1476-5381.1991.tb12292.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Newberry N. R., Cheshire S. H., Gilbert M. J. Evidence that the 5-HT3 receptors of the rat, mouse and guinea-pig superior cervical ganglion may be different. Br J Pharmacol. 1991 Mar;102(3):615–620. doi: 10.1111/j.1476-5381.1991.tb12221.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pinkus L. M., Sarbin N. S., Gordon J. C., Munson H. R., Jr Antagonism of [3H]zacopride binding to 5-HT3 recognition sites by its (R) and (S) enantiomers. Eur J Pharmacol. 1990 Apr 10;179(1-2):231–235. doi: 10.1016/0014-2999(90)90425-6. [DOI] [PubMed] [Google Scholar]
  16. Rhodes K. F., Coleman J., Lattimer N. A component of 5-HT-evoked depolarization of the rat isolated vagus nerve is mediated by a putative 5-HT4 receptor. Naunyn Schmiedebergs Arch Pharmacol. 1992 Nov;346(5):496–503. doi: 10.1007/BF00169003. [DOI] [PubMed] [Google Scholar]
  17. Richardson B. P., Engel G., Donatsch P., Stadler P. A. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature. 1985 Jul 11;316(6024):126–131. doi: 10.1038/316126a0. [DOI] [PubMed] [Google Scholar]
  18. Smith W. W., Sancilio L. F., Owera-Atepo J. B., Naylor R. J., Lambert L. Zacopride, a potent 5-HT3 antagonist. J Pharm Pharmacol. 1988 Apr;40(4):301–302. doi: 10.1111/j.2042-7158.1988.tb05253.x. [DOI] [PubMed] [Google Scholar]
  19. Waeber C., Pinkus L. M., Palacios J. M. The (S)-isomer of [3H]zacopride labels 5-HT3 receptors with high affinity in rat brain. Eur J Pharmacol. 1990 Jun 8;181(3):283–287. doi: 10.1016/0014-2999(90)90090-s. [DOI] [PubMed] [Google Scholar]
  20. Watling K. J., Aspley S., Swain C. J., Saunders J. [3H]quaternised ICS 205-930 labels 5-HT3 receptor binding sites in rat brain. Eur J Pharmacol. 1988 May 10;149(3):397–398. doi: 10.1016/0014-2999(88)90677-2. [DOI] [PubMed] [Google Scholar]
  21. Young R., Johnson D. N. Anxiolytic-like activity of R(+)- and S(-)-zacopride in mice. Eur J Pharmacol. 1991 Aug 29;201(2-3):151–155. doi: 10.1016/0014-2999(91)90338-q. [DOI] [PubMed] [Google Scholar]

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