Skip to main content
SpringerLink
Log in

The production of an alternative laboratory model of the Parkinson syndrome using a new benzylimidoylurea derivative LON 954

  • Animal Studies
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON 954) causes a reproducible rest tremor in mice, of rapid onset and short duration with no associated rigidity or akinesia and in the absence of any marked changes in body temperature or accompanying peripheral parasympathomimetic effects. This tremor can be antagonised by the dopamine receptor agonists l-Dopa, bromocriptine, nomifensine and piribedil, as well as by anticholinergic anti-Parkinson drugs having an inhibitory effect on dopamine uptake such as benapryzine and benztropine. In contrast, benzhexol, orphenadrine and amantadine had no effect. LON 954 appears to be more specific than oxotremorine for the detection of drugs having therapeutic potential in the treatment of Parkinson's disease, particularly those exerting their effect through dopaminergic systems. An antagonist (BS 100–141), which is a structural isomer of LON 954, is also described.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Baldessarini, R. J., Lipinski, J. F., Chase, E. U.: Effects of amantadine hydrochloride on catecholamine metabolism in the brain of the rat. Biochem. Pharmacol. 21, 77–88 (1972)

    Google Scholar 

  • Barnett, A., Goldstein, J.: Head-turning induced by electrical stimulation of the caudate nucleus and its antagonism by anti-Parkinson drugs. J. Pharmacol. exp. Ther. 194, 296–302 (1975)

    Google Scholar 

  • Bernheimer, H., Hornykiewicz, O.: Herabgesetzte Konzentration der Homovanillinsäure im Gehirn von Parkinson-kranken Menschen als Ausdruck der Störung des zentralen Dopaminstoffwechsels. Klin. Wschr. 43, 711–715 (1965)

    Google Scholar 

  • Brimblecombe, R. W., Pinder, R. M.: Tremors and tremorogenic agents. Bristol: Scientechnica 1972

    Google Scholar 

  • Butcher, R. W., Sutherland, E. W.: Adenosin 3′,5′-phosphate in biological materials. J. biol. Chem. 237, 1244–1250 (1962)

    Google Scholar 

  • Clane, D. B., Teychenne, P. F., Claveria, L. E., Eastman, R., Greenacre, J. K., Petrie, A.: Bromocriptine in Parkinsonism. Brit. med. J. 1974IV, 442–444

  • Corenzi, A., Cheney, D. L., Costa, E., Guidotti, A., Racazni, G.: Action of opiates, antipsychotics, amphetamine and apomorphine on dopamine receptors in rat striatum: in vivo changes of 3′,5′-cyclic AMP content and acetylcholine turnover rate. Neuropharmacology 14, 927–939 (1975)

    Google Scholar 

  • Costall, B., Naylor, R. J.: Specific asymmetric behaviour induced by the direct chemical stimulation of neostriatal dopaminergic mechanisms. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 83–98 (1974)

    Google Scholar 

  • Cotzias, G. C., Papavasiliou, P. S., Fehling, C., Kaufman, B., Mena, I.: Similarities between neurologic effects of l-dopa and of apomorphine. New Engl. J. Med. 282, 31–33 (1970)

    Google Scholar 

  • Cotzias, G. C., Papavasiliou, P. S., Tolosa, E. S., Mendez, J. F., Bell-Midura, M.: Treatment of Parkinsons disease with aporphines. Possible role of growth hormone. New Engl. J. Med. 294, 567–572 (1976)

    Google Scholar 

  • Cotzias, G. C., Van Woert, M. D., Schiffer, L. M.: Aromatic amino acids and modification of Parkinsonism. New Engl. J. Med. 276, 374–379 (1967)

    Google Scholar 

  • Coward, D. M., Doggett, N. S., Sayers, A. C.: The pharmacology of LON 954 [N-carbamoyl-2-(2,6-dichlorophenyl) acetamide hydrochloride]—a new tremorogenic agent. Arzneimittel-Forsch. (in press)

  • Coyle, J. T., Snyder, S. H.: Anti-Parkinson drugs: Inhibition of dopamine uptake in the corpus straitum as a possible mechanism of action. Science 166, 899–901 (1969)

    Google Scholar 

  • Curzon, G.: The biochemistry of dyskinesias. Int. Rev. Neurobiol. 10, 323–370 (1967)

    Google Scholar 

  • Doggett, N. S., Spencer, P. S. J.: Pharmacological properties of centrally-administered agents which interfere with neurotransmitter function: a comparison with the central depressant effects of ouabain. Brit. J. Pharmacol. 47, 26–38 (1973)

    Google Scholar 

  • Duvoisin, R. C.: A review of drug therapy in Parkinsonism. Bull. N.Y. Acad. Med. 41, 898–910 (1965)

    Google Scholar 

  • Ehringer, H., Hornykiewicz, O.: Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des Extrapyramidalen Systems. Klin. Wschr. 38, 1236–1239 (1960)

    Google Scholar 

  • Farnebo, L. O., Fuxe, K., Goldstein, M., Hamberger, B., Ungerstedt, U.: Dopamine and noradrenaline releasing action of amantadine in the central and peripheral nervous system: a possible mode of action in Parkinsons disease. Europ. J. Pharmacol. 16, 27–38 (1971)

    Google Scholar 

  • Fletcher, E. A., Redfern, P. H.: The effects of amantadine on the uptake of dopamine and noradrenaline by rat brain homogenates. J. Pharm. Pharmacol. 22, 957–959 (1970)

    Google Scholar 

  • Friedman, A. H., Everett, G. M.: Pharmacological aspects of Parkinsonism. Advanc. Pharmacol. 3, 83–127 (1964)

    Google Scholar 

  • Fuxe, K., Ungerstedt, U.: Histochemical, biochemical and functional studies on central monoamine neurones after acute and chronic amphetamine administration. In: International Symposium on amphetamines and related compounds, E. Costa and S. Garattini, eds., pp. 257–288. New York: Raven Press 1970

    Google Scholar 

  • Heimans, R. L. H., Rand, M. J., Fennessy, M. R.: Effects of amantadine on uptake and release of dopamine by a particulate fraction of rat basal ganglia. J. Pharm. Pharmacol. 24, 875–879 (1972)

    Google Scholar 

  • Hornykiewicz, O.: Die topische Lokalisation und das Verhalten von Noradrenalin und Dopamin (3-Hydroxytyramin) in der Substantia nigra des normalen und Parkinson-kranken Menschen. Wien. klin. Wschr. 75, 309–312 (1963)

    Google Scholar 

  • Jori, A., Cecchetti, G., Dolfini, E., Monti, E., Garattini, S.: Effect of Piribedil and one of its metabolites on the concentration of Homovanillic acid in the rat brain. Europ. J. Pharmacol. 27, 245–248 (1974)

    Google Scholar 

  • Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopamine-sensitive Adenyl cyclase in caudate nucleus of rat brain, and its similarity to the “Dopamine Receptor”. Proc. nat. Acad. Sci. (Wash.) 69, 2145–2149 (1972)

    Google Scholar 

  • Lieberman, A., Miyamoto, T., Battista, A. F., Goldstein, M.: Studies on the antiparkinsonian efficacy of lergotrile. Neurology (Minneap.) 25, 459–462 (1975)

    Google Scholar 

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

    Google Scholar 

  • Ordenstein, L.: Sur la paralysie agitante et la sclerose en plaques generaliséc. M.D. thesis Paris, Martinet 1867

    Google Scholar 

  • Palfreyman, M. G., Palfreyman, E. S., Clark, M. S. G.: Effects of Benapryzine, a new anti-Parkinson drug on dopamine uptake into corpus striatum. Europ. J. Pharmacol. 28, 379–383 (1974)

    Google Scholar 

  • Papeschi, R.: Amantadine may stimulate dopamine and noradrenaline receptors. Neuropharmacology 13, 77–84 (1974)

    Google Scholar 

  • Scatton, B., Cheramy, A., Beeson, M. J., Glowinski, J.: Increased synthesis and release of dopamine in the striatum of the rat after amantadine treatment. Europ. J. Pharmacol. 13, 131–133 (1970)

    Google Scholar 

  • Scholtysik, G., Lauener, H., Eichenberger, E., Bürki, H., Salzmann, R., Müller-Schweinitzer, E., Waite, R.: Pharmacological actions of the antihypertensive agent N-amidino-2-(2,6-dichlorophenyl) acetamide hydrochloride, (BS 100–141). Arzneimittel-Forsch. 25, 1483–1491 (1975)

    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, 442–445 (1965)

    Google Scholar 

  • Stern, P.: Methods for evaluating anti-tremorogenic drugs. In: Methods in drug evaluation, P. Mantegazza and F. Piccinini, eds., pp. 263–269. Amsterdam: North Holland 1966

    Google Scholar 

  • Symchowicz, S., Korduba, C. A., Veals, J.: The effect of amantadine on radio-labelled biogenic amines in rat brain. Europ. J. Pharmacol. 21, 155–160 (1973)

    Google Scholar 

  • Tasker, R. R., Kerterzs, A.: The physiology of tremorine-induced tremor. J. Neurosurg. 22, 449–457 (1965)

    Google Scholar 

  • Ungerstedt, U., Arbuthnott, G. W.: Quantitative recording of rotational behaviour in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 435–493 (1970)

    Google Scholar 

  • Vernier, G. U., Unna, K. R.: The central nervous system effects of drugs in monkeys with surgically induced tremor: atropine and other antitremor agents. Arch. int. Pharmacodyn. 141, 30–55 (1967)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Applied Pharmacology, Welsh School of Pharmacy, University of Wales Institute of Science and Technology, King Edward VII Avenue, CF1 3NU, Cardiff, UK

    D. M. Coward & N. S. Doggett

Authors
  1. D. M. Coward
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. S. Doggett
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coward, D.M., Doggett, N.S. The production of an alternative laboratory model of the Parkinson syndrome using a new benzylimidoylurea derivative LON 954. Psychopharmacology 52, 165–171 (1977). https://doi.org/10.1007/BF00439104

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00439104

Key words

Search

Navigation