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

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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.

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References

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Ellinwood, E. H., Jr.: Amphetamine Psychosis: I. Description of the individuals and process. J. nerv. ment. Dis. 144, 273–283 (1967)

    Google Scholar 

  • Ernst, A. M.: Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia (Berl.) 10, 316–323 (1967)

    Google Scholar 

  • Fisher, Sir R. A., Yates, F.: Statistical tables for biological, agricultural and medical research. Sixth edition, p. 134. Darien, Conn.: Hafner 1970

    Google Scholar 

  • 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 

  • 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 

  • 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 1970

    Google Scholar 

  • 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 1974

  • Janssen, P. A. J.: The pharmacology of haloperidol. Intern. J. Neuropsychiat. 3, Suppl. 1, S10-S18 (1967)

    Google Scholar 

  • 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 1970

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 1970

    Google Scholar 

  • 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 

  • Litchfield, J. T., Wilcoxon, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949)

    Google Scholar 

  • 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 

  • Morpurgo, C.: Effects of antiparkinson drugs on a phenothiazine-induced catatonic reaction. Arch. int. Pharmacodyn. 137, 84–90 (1962)

    Google Scholar 

  • Morpurgo, C.: Drug-induced modifications of discriminated avoidance behavior in rats. Psychopharmacologia (Berl.) 8, 91–99 (1965)

    Google Scholar 

  • 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 1970

    Google Scholar 

  • 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 

  • 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 

  • 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 1970

    Google Scholar 

  • Randrup, A., Mundvad, I.: Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia (Berl.) 11, 300–310 (1967)

    Google Scholar 

  • Randrup, A., Munkvad, I.: Behavioural stereotypies induced by pharmacological agents. Pharmakopsychiat. Neuropsychopharmak. 1, 18–26 (1968)

    Google Scholar 

  • 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 1970

    Google Scholar 

  • Randrup, A., Munkvad, I., Udsen, P.: Adrenergic mechanisms and amphetamine-induced abnormal behaviour. Acta pharmacol. (Kbh.) 20, 145–157 (1963)

    Google Scholar 

  • 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 1967

    Google Scholar 

  • 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 1970

    Google Scholar 

  • 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 

  • Scheckel, C. L.: Preclinical psychopharmacology. In: Principles of psychopharmacology, W. G. Clark, ed., pp. 235–253. New York: Academic Press 1970

    Google Scholar 

  • Scheel-Krüger, J., Randrup, A.: Stereotype hyperactive behaviour produced by dopamine in the absence of noradrenaline. Life Sci. 6, 1389–1398 (1967a)

    Google Scholar 

  • 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 

  • Snyder, S. H.: Catecholamines in the brain as mediators of amphetamine psychosis. Arch. gen. Psychiat. 27, 169–179 (1972)

    Google Scholar 

  • Snyder, S. H.: Amphetamine psychosis: A “model” schizophrenia mediated by catecholamines. Amer. J. Psychiat. 130, 61–67 (1973)

    Google Scholar 

  • 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 

  • 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)

  • 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 

  • 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 1974

    Google Scholar 

  • 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 

  • Wirth, W., Gösswald, U., Hörlein, U., Risse, K. H., Kreiskott, H.: Zur Pharmakologie acylierter Phenothiazinderivate. Arch. int. Pharmacodyn. 115, 1–31 (1958)

    Google Scholar 

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  1. Department of Pharmacology, Ayerst Research Laboratories, Montreal, Canada

    Katherine Voith & Francis Herr

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  1. Katherine Voith
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  2. Francis Herr
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Voith, K., Herr, F. The behavioral pharmacology of butaclamol hydrochloride (AY-23,028), a new potent neuroleptic drug. Psychopharmacologia 42, 11–20 (1975). https://doi.org/10.1007/BF00428819

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