Skip to main content
SpringerLink
Log in

Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171

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

Abstract

The neurochemical characteristics of a new bicyclic phthalane derivative — Lu 10-171 [1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalan-carbonitrile; citalopram] — have been investigated. Lu 10-171 and its metabolites were compared with tricyclic thymoleptics in several tests for serotonin (5-HT), noradrenaline (NA), and dopamine (DA) uptake inhibition in vitro and in vivo. Lu 10-171 is a very potent and completely selective inhibitor of the 5-HT reuptake mechanism, being 2–10 times as active as chlorimipramine. The metabolites of Lu 10-171 show weak 5-HT uptake inhibiting properties. Lu 10-171 and its metabolites are devoid of NA uptake inhibiting properties and in this respect they clearly differ from the tricyclic anti-depressants, which possess effects both on 5-HT and NA uptake. The inhibition of 5-HT uptake in vitro is competitive and not connected with an increased efflux of 5-HT. Lu 10-171 and its metabolites only inhibit DA uptake in extremely high concentrations and in this respect they are even weaker than chlorimipramine and other tricyclic thymoleptics. Like the tri-cyclic thymoleptics, Lu 10-171 is without effect on MAO and does not change the endogenous levels of brain monoamines. Due to the selective action on 5-HT uptake, Lu 10-171 seems to be a valuable tool in studying the role of central 5-HT neurone systems in experimental neuropharmacology as well as in the ethiology of depressive illness.

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

  • Åsberg, M., Bertilsson, L., Tuck, D., Cronholm, B., Sjöqvist, F.: Indolamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline. Clin. Pharmacol. Ther. 14, 277–286 (1973)

    Google Scholar 

  • Aghajanian, G. K.: Influence of drugs on the firing of serotonin-containing neurons in brain. Fed. Proc. 31, 91–96 (1972)

    Google Scholar 

  • Ahtee, L., Saarnivaara, L.: The effect of drugs upon the uptake of 5-hydroxytryptamine and metaraminol by human platelets. J. Pharm. Pharmacol. 23, 495–501 (1971)

    Google Scholar 

  • Andén, N.-E., Fuxe, K., Henning, M.: Mechanisms of noradrenaline and 5-hydroxytryptamine disappearance induced by α-methyl-dopa and α-methyl-metatyrosine. Europ. J. Pharmacol. 8, 302–309 (1969)

    Google Scholar 

  • Atack, C. V.: The determination of dopamine by a modification of the dihydroxyindole fluorimetric assay. Brit. J. Pharmacol. 48, 699–714 (1973)

    Google Scholar 

  • Campbell, I. C., Todrick, A.: On the pharmacology and biochemistry of the amine uptake mechanism in human blood platelets. Brit. J. Pharmacol. 49, 279–287 (1973)

    Google Scholar 

  • Carlsson, A.: Structural specificity for inhibition of (14C)-5-hydroxytryptamine uptake by cerebral slices. J. Pharm. Pharmacol. 22, 729–732 (1970)

    Google Scholar 

  • Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of anti-depressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-α-ethyl-meta-tyramine. Europ. J. Pharmacol. 5, 357–366 (1969a)

    Google Scholar 

  • Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,α-dimethyl-meta-tyramine. Europ. J. Pharmacol. 5, 367–373 (1969b)

    Google Scholar 

  • Carlsson, A., Fuxe, K., Hamberger, B., Malmfors, T.: Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine-resistant uptake mechanism of central and peripheral monoamine neurones in vivo and in vitro. Brit. J. Pharmacol. 36, 18–28 (1969c)

    Google Scholar 

  • Christensen, A. V., Fjalland, B., Pedersen, V., Danneskiold-Samsøe, P., Svendsen, O.: Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties. Europ. J. Pharmacol. 41, (1977) (in press)

  • Frisk-Holmberg, M.: Inhibition of the uptake of biogenic amines into mast cells by tricyclic psychoactive drugs. Acta physiol. scand. 85, 446–454 (1972)

    Google Scholar 

  • Horn, A. S., Coyle, J. T., Snyder, S. H.: Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons. Molec. Pharmacol. 7, 66–80 (1971)

    Google Scholar 

  • Hyttel, J.: Endogenous levels and turnover of catecholamines in mouse brain after repeated administration of haloperidol. Psychopharmacologia (Berl.) 36, 237–241 (1974)

    Google Scholar 

  • Hyttel, J.: Effect of a selective 5-HT uptake inhibitor — Lu 10-171 —on rat brain 5-HT turnover. Acta pharmacol. (Kbh.) 40, (1977) (in press)

  • Hyttel, J., Fjalland, B.: Central 5-HT decarboxylase inhibiting properties of Ro 4-4602 in relation to 5-HTP potentiation in mice. Europ. J. Pharmacol. 19, 112–114 (1972)

    Google Scholar 

  • Jonsson, G., Sachs, S.: Uptake and accumulation of 3H-6-Hydroxydopamine in adrenergic nerves. Europ. J. Pharmacol. 16, 55–62 (1971)

    Google Scholar 

  • Kielholz, P. Pöldinger, W.: Die Behandlung endogener Depressionen mit Psychopharmaka. Dtsch. med. Wschr. 174, 701–704 (1968a)

    Google Scholar 

  • Kielholz, P., Pöldinger, W.: Pharmacotherapy of endogenous depression. Comprehens. Psychiat. 9, 179–186 (1968b)

    Google Scholar 

  • Krajl, M.: A rapid microfluorimetric determination of monoamine oxidase. Biochem. Pharmacol. 14, 1683–1685 (1965)

    Google Scholar 

  • Lapin, I. P., Oxenkrug, G. F.: Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1969I, 132–136

  • Lidbrink, P., Jonsson, G., Fuxe, K.: The effect of imipramine-like drugs and antihistamine drugs on uptake mechanisms in the central noradrenaline and 5-hydroxytryptamine neurons. Neuropharmacology 10, 521–536 (1971)

    Google Scholar 

  • Lingjaerde, O.: Inhibitory effect of two newer antidepressants, Lu 5-003 and Lu 3-010, on serotonin uptake in human blood platelets in vitro. Psychopharmacologia (Berl.) 17, 94–99 (1970)

    Google Scholar 

  • Lingjaerde, O.: Studies on the uptake of serotonin in human blood platelets in vitro, pp. 1–55. Dr. Thesis, Universitetsforlaget, Oslo (1971)

    Google Scholar 

  • Maxwell, R. A., Eckhardt, S. B., Chaplin, E., Burcsu, J.: Inhibition of the uptake of norepinephrine by the adrenergic nerves in rabbit aorta. In: Proc. Symp. Physiol. Vasc. Neuroeffector Systems. Interlaken 1969, pp. 98–110. Basel: Karger 1971

    Google Scholar 

  • Maxwell, R. A., Eckhardt, S. B., Hite G.: Kinetic and thermo-dynamic considerations regarding the inhibition by tricyclic antidepressants of the uptake of norepinephrine by the adrenergic nerves in rabbit aortic strips. J. Pharmacol. exp. Ther. 171, 62–69 (1970)

    Google Scholar 

  • Mellström, B., Eksborg, S.: Determination of chlorimipramine and desmethylchlorimipramine in human plasma by ion-pair partition chromatography. J. Chromatogr. 116, 475–479 (1976)

    Google Scholar 

  • Miller, I., Freund, J. E.: Probability and statistics for engineers, p. 174. Engle Wood Cliffs: Prentice-Hall 1965

    Google Scholar 

  • Petersen, P. V., Lassen, N., Ammitzbøll, T., Møller Nielsen, I., Nymark, M., Pedersen, V., Franck, K. F.: Further pharmacological studies of bicyclic thymoleptics. Acta pharmacol. (Kbh.) 28, 241–248 (1970)

    Google Scholar 

  • Petersen, P. V., Lassen, N., Hansen, V., Huld, T., Hjortkjaer, J., Holmblad, J., Møller Nielsen, I., Nymark, M., Pedersen, V., Jørgensen, A., Houghs, W.: Pharmacological studies of a new series of bicyclic thymoleptics. Acta pharmacol. (Kbh.) 24, 121–133 (1966)

    Google Scholar 

  • Pletscher, A., Prada, M., Berneis, K. H., Tranzer, J. P.: New aspects on the storage of 5-hydroxytryptamine in blood platelets. Experientia (Basel) 27, 993–1002 (1971)

    Google Scholar 

  • Van Praag, H. M., Korf, J.: Endogenous depression with and without disturbances in the 5-hydroxytryptamine metabolism: A new biochemical classification. Psychopharmacologia (Berl.) 19, 148–152 (1971)

    Google Scholar 

  • Sachs, C.: Noradrenaline uptake mechanisms in the mouse atrium. A biochemical and histochemical study. Acta physiol. scand., Suppl. 341, 1–67 (1970)

    Google Scholar 

  • Sachs, C., Jonsson, G.: Noradrenaline uptake mechanisms in human atrium. Acta pharmacol. (Kbh.) 31, 456–470 (1972)

    Google Scholar 

  • Salama, A. I., Insalaco, J. R., Maxwell, R. A.: Concerning the molecular requirements for the inhibition of the uptake of racemic 3H-norepinephrine into rat cerebral cortex slices by tricyclic antidepressants and related compounds. J. Pharmacol. exp. Ther. 178, 474–481 (1971)

    Google Scholar 

  • Schildkraut, J. J.: The catecholamine hypothesis of affective disorders: A review of supporting evidence. Amer. J. Psychiat. 122, 509–522 (1965)

    Google Scholar 

  • Schildkraut, J. J.: Neuropharmacology of the affective disorders. Ann. Rev. Pharmacol. 13, 427–454 (1973)

    Google Scholar 

  • Schubert J., Nybäck, H., Sedvall, G.: Effect of antidepressant drugs on accumulation and disappearance of monoamines formed in vivo from labelled precursors in mouse brain. J. Pharm. Pharmacol. 22, 136–139 (1970)

    Google Scholar 

  • Strömgren, L. S., Friderichsen, T.: Lu 5-003 i antidepressiv terapi. Nord. Psykiat. Tidskr. 25, 119–128 (1971)

    Google Scholar 

  • Todrick, A., Tait, A. C.: The inhibition of human platelet 5-hydroxytryptamine uptake by tricyclic antidepressive drugs. The relation between structure and potency. J. Pharm. Pharmacol. 21, 751–762 (1969)

    Google Scholar 

  • Tuomistro, J.: A new modification for studying 5-HT uptake by blood platelets: a re-evaluation of tricyclic antidepressants as uptake inhibitors. J. Pharm. Pharmacol. 26, 92–100 (1974)

    Google Scholar 

  • Zavidovskaya, G. I.: The use of Lu 3-010 in the treatment of depressive states. Zh. Nevropat. Psikhiat. 69, 594–598 (1969)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, H. Lundbeck & Co. A/S, Ottiliavej 7-9, DK-2500, Copenhagen-Valby, Denmark

    John Hyttel

Authors
  1. John Hyttel
    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

Hyttel, J. Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171. Psychopharmacology 51, 225–233 (1977). https://doi.org/10.1007/BF00431629

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00431629

Key words

Search

Navigation