Advertisement

Psychopharmacologia

, Volume 42, Issue 1, pp 11–20 | Cite as

The behavioral pharmacology of butaclamol hydrochloride (AY-23,028), a new potent neuroleptic drug

  • Katherine Voith
  • Francis Herr
Animal Studies

Abstract

Butaclamol hydrochloride (AY-23,028) is a member of a new chemical class for which antipsychotic activity in humans has recently been demonstrated. The compound antagonized amphetamine-induced stereotyped behavior in rats, amphetamine toxicity in aggregated mice and apomorphine-induced emesis in dogs. It depressed both discriminated avoidance and continuous lever-pressing behavior in rats and inhibited ambulation and rearing in the open field. At higher doses, AY-23,028 induced catalepsy. Adrenergic blocking activity, measured by the antagonism of epinephrine-induced mortality, was weak. These pharmacological actions are characteristic of neuroleptic drugs. In the dose range where the aforementioned effects were observed, AY-23,028 did not antagonize either the tetrabenazine-induced ptosis or the tremorine syndrome and did not cause either hypothermia or ataxia. The potency and onset of action of AY-23,028 were comparable to those of fluphenazine but AY-23,028 was of longer duration. The results are discussed in relation to current concepts of neuroleptic mechanisms.

Key words

Pharmacology Neuroleptic Butaclamol Hydrochloride (AY-23,028) 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andén, N.-E., Rubenson, A., Fuxe, K., Hökfelt, T.: Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol. 19, 627–629 (1967)Google Scholar
  2. Barry, H., III, Steenberg, M. L., Manian, A. A., Buckley, J. P.: Effects of chlorpromazine and three metabolites on behavioral responses in rats. Psychopharmacologia (Berl.) 34, 351–360 (1974)Google Scholar
  3. Bruderlein, F., Humber, L., Voith, K.: Neuroleptic agents of the benzocycloheptapyridoisoquinoline series: I. The syntheses, stereochemical and structural requirements for activity of Butaclamol and related compounds. J. med. Chem. 18, 185–188 (1975)Google Scholar
  4. Del Rio, J., Fuentes, J. A.: Further studies on the antagonism of stereotyped behaviour induced by amphetamine. Europ. J. Pharmacol. 8, 73–78 (1969)Google Scholar
  5. Dunham, N. W., Miya, T. S.: A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Amer. pharm. Ass., Sci. Ed. 46, 208–209 (1957)Google Scholar
  6. Ellinwood, E. H., Jr.: Amphetamine Psychosis: I. Description of the individuals and process. J. nerv. ment. Dis. 144, 273–283 (1967)Google Scholar
  7. Ernst, A. M.: Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia (Berl.) 10, 316–323 (1967)Google Scholar
  8. Fisher, Sir R. A., Yates, F.: Statistical tables for biological, agricultural and medical research. Sixth edition, p. 134. Darien, Conn.: Hafner 1970Google Scholar
  9. Fog, R.: On stereotypy and catalepsy: studies on the effect of amphetamines and neuroleptics in rats. Acta neurol. scand. 48, Suppl. 50 (1972)Google Scholar
  10. Herman, Z. S.: Influence of some psychotropic and adrenergic blocking agents upon amphetamine stereotyped behaviour in white rats. Psychopharmacologia (Berl.) 11, 136–142 (1967)Google Scholar
  11. Hornykiewicz, O., Markham, C. H., Clark, W. G., Fleming, R. M.: Mechanisms of extrapyramidal side effects of therapeutic agents. In: Principles of psychopharmacology, W. G. Clark, ed., pp. 585–595. New York: Academic Press 1970Google Scholar
  12. Humber, L., Bruderlein, F.: Butaclamol hydrochloride, a novel neuroleptic agent. Synthesis and stereochemistry, Abstract MEDI-5, Symposium on central dopamine receptors: stimulants and antagonists, 167th A.C.S. National Meeting, Los Angeles 1974Google Scholar
  13. Janssen, P. A. J.: The pharmacology of haloperidol. Intern. J. Neuropsychiat. 3, Suppl. 1, S10-S18 (1967)Google Scholar
  14. Janssen, P. A. J.: Chemical and pharmacological classification of neuroleptics. In: Modern problems of pharmacopsychiatry (The neuroleptics), vol. 5, D. P. Bobon, P. A. J. Janssen and J. Bobon, eds., pp. 33–44. Basel: Karger 1970Google Scholar
  15. Janssen, P. A. J., Jageneau, A. H. M., Schellekens, K. H. L.: Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenylpiperidino)-butyrophenone. Part IV. Influence of haloperidol (R1625) and of chlorpromazine on the behaviour of rats in an unfamiliar “open field” situation. Psychopharmacologia (Berl.) 1, 389–392 (1960)Google Scholar
  16. Janssen, P. A. J., Niemegeers, C. J. E., Schellekens, K. H. L.: Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part I: “Neuroleptic activity spectra” for rats. Arzneimittel-Forsch. 15, 104–117 (1965a)Google Scholar
  17. Janssen, P. A. J., Niemegeers, C. J. E., Schellekens, K. H. L.: Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part II: “Neuroleptic activity spectra” for dogs. Arzneimittel-Forsch. 15, 1196–1206 (1965b)Google Scholar
  18. Julou, L.: On the interaction between neuroleptics and antiparkinson drugs. In: Modern problems of pharmacopsychiatry (The neuroleptics), vol. 5, D. P. Bobon, P. A. J. Janssen and J. Bobon, eds., pp. 50–54. Basel: Karger 1970Google Scholar
  19. Klawans, H. J., Jr.: The pharmacology of parkinsonism. In: The pharmacology of extrapyramidal movement disorders. Monographs in neural sciences, vol. 2, pp. 7–48. Basel: S. Karger 1973.Google Scholar
  20. Litchfield, J. T., Wilcoxon, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949)Google Scholar
  21. Mielke, D. H., Gallant, D. M., Oelsner, T., Kessler, C. M., Tomlinson, W. K., Cohen, G. H.: Butaclamol hydrochloride (AY-23,028): an early evaluation in severely ill schizophrenics. Dis. nerv. Syst. 36, 7–8 (1975)Google Scholar
  22. Morpurgo, C.: Effects of antiparkinson drugs on a phenothiazine-induced catatonic reaction. Arch. int. Pharmacodyn. 137, 84–90 (1962)Google Scholar
  23. Morpurgo, C.: Drug-induced modifications of discriminated avoidance behavior in rats. Psychopharmacologia (Berl.) 8, 91–99 (1965)Google Scholar
  24. Munkvad, I.: Neuroleptics in the treatment of schizophrenia. In: Modern problems of pharmacopsychiatry (The neuroleptics), vol. 5, D. P. Bobon, P. A. J. Janssen and J. Bobon, eds., pp. 44–47. Basel: Karger 1970Google Scholar
  25. Niemegeers, C. J. E., Verbruggen, F. J., Janssen, P. A. J.: The influence of various neuroleptic drugs on shock avoidance responding in rats. I. Nondiscriminated Sidman avoidance procedure. Psychopharmacologia (Berl.) 16, 161–174 (1969)Google Scholar
  26. Proctor, C. D., Potts, J. L., Lundy, R. O., Greenfield, E. J.: Phenothiazine tranquilizer reversal of amphetamine toxicity for aggregated mice. Arch. int. Pharmacodyn. 163, 79–86 (1966)Google Scholar
  27. Randrup, A.: Role of brain dopamine in the antipsychotic effect of neuroleptics, evidence from studies of amphetamine-neuroleptic interaction. In: Modern problems of pharmacopsychiatry (The neuroleptics), vol. 5, D. P. Bobon, P. A. J. Janssen and J. Bobon, eds., pp. 60–65. Basel: Karger 1970Google Scholar
  28. Randrup, A., Mundvad, I.: Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia (Berl.) 11, 300–310 (1967)Google Scholar
  29. Randrup, A., Munkvad, I.: Behavioural stereotypies induced by pharmacological agents. Pharmakopsychiat. Neuropsychopharmak. 1, 18–26 (1968)Google Scholar
  30. Randrup, A., Munkvad, I.: Biochemical, anatomical and psychological investigations of stereotyped behavior induced by amphetamines. In: Intern. symp. on amphetamines and related compounds, E. Costa and S. Garattini, eds., pp. 695–713. New York: Raven Press 1970Google Scholar
  31. Randrup, A., Munkvad, I., Udsen, P.: Adrenergic mechanisms and amphetamine-induced abnormal behaviour. Acta pharmacol. (Kbh.) 20, 145–157 (1963)Google Scholar
  32. van Rossum, J. M.: The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Neuro-psycho-pharmacology, H. Brill, ed., International Congress Series No. 129, pp. 321–329. Amsterdam: Excerpta Medica Foundation 1967Google Scholar
  33. van Rossum, J. M., Janssen, P. A. J., Boissier, J. R., Julou, L., Loew, D. M., MØller Nielsen, I., Munkvad, I., Randrup, A., Stille, G., Tedeschi, D. H.: Pharmacology. In: Modern problems of pharmacopsychiatry (The neuroleptics), vol. 5, D. P. Bobon, P. A. J. Janssen and J. Bobon, eds., pp. 23–32. Basel: Karger 1970Google Scholar
  34. Rubin, B., Malone, M. H., Waugh, M. H., Burke, J. C.: Bioassay of rauwolfia roots and alkaloids. J. Pharmacol. exp. Ther. 120, 125–136 (1957)Google Scholar
  35. Scheckel, C. L.: Preclinical psychopharmacology. In: Principles of psychopharmacology, W. G. Clark, ed., pp. 235–253. New York: Academic Press 1970Google Scholar
  36. Scheel-Krüger, J., Randrup, A.: Stereotype hyperactive behaviour produced by dopamine in the absence of noradrenaline. Life Sci. 6, 1389–1398 (1967a)Google Scholar
  37. Scheel-Krüger, J., Randrup, A.: Production of a stereotyped behaviour in rats by dopamine in the absence of noradrenaline. Acta pharmacol. (Kbh.) 25, Suppl. 4, 61 (1967b)Google Scholar
  38. Snyder, S. H.: Catecholamines in the brain as mediators of amphetamine psychosis. Arch. gen. Psychiat. 27, 169–179 (1972)Google Scholar
  39. Snyder, S. H.: Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Amer. J. Psychiat. 130, 61–67 (1973)Google Scholar
  40. Spencer, P. S. J.: Activity of centrally acting and other drugs against tremor and hypothermia induced in mice by tremorine. Brit. J. Pharmacol. 25, 442–455 (1965)Google Scholar
  41. Sulser, F., Bass, A. D.: Pharmacodynamics and biochemical considerations on the mode of action of reserpine-like drugs. In: Psychopharmacology: a review of progress, 1957–1967, D. H., Efron, ed., Public Health Service Publication No. 1836, pp. 1065–1075 (1968)Google Scholar
  42. Vernier, V. G., Alleva, F. R., Hanson, H. M., Stone, C. A.: Pharmacological actions of amitriptyline, noramitriptyline and imipramine. Fed. Proc. 21, 419 (1962)Google Scholar
  43. VinaŘ, O., Kršiak, M.: Prediction of neuroleptic effects from animal data. In: The phenothiazines and structurally related drugs. I. S. Forrest, C. J. Carr and E. Usdin, eds., pp. 675–683. New York: Raven Press 1974Google Scholar
  44. Voith, K., Herr, F.: The effect of various antidepressant drugs upon the tetrabenazine-suppressed conditioned avoidance response in rats. Psychopharmacologia (Berl.) 20, 253–265 (1971)Google Scholar
  45. Wirth, W., Gösswald, U., Hörlein, U., Risse, K. H., Kreiskott, H.: Zur Pharmakologie acylierter Phenothiazinderivate. Arch. int. Pharmacodyn. 115, 1–31 (1958)Google Scholar

Copyright information

© Springer-Verlag 1975

Authors and Affiliations

  • Katherine Voith
    • 1
  • Francis Herr
    • 1
  1. 1.Department of PharmacologyAyerst Research LaboratoriesMontrealCanada

Personalised recommendations