Skip to main content
SpringerLink
Log in

Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized.

2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.

3. DOV 102,677 is a novel, “triple” uptake inhibitor that suppresses [3H]dopamine (DA), [3H]norepinephrine (NE) and [3H]serotonin (5-HT) uptake by recombinant human transporters with IC50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days).

4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity.

5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.

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

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

REFERENCES

  • Axelrod, J., Whitby, L. G., and Hertting, G. (1961). Effect of psychotropic drugs on the uptake of 3H-norepinephrine by tissues. Science 133:383–384.

    Article  PubMed  CAS  Google Scholar 

  • Beer, B., Stark, J., Krieter, P., Czobor, P., Beer, G., Lippa, A., and Skolnick, P. (2004). DOV 216,303, a “triple” reuptake inhibitor: Safety, tolerability, and pharmacokinetic profile. J. Clin. Pharmacol. 44:1360–1367.

    Article  PubMed  CAS  Google Scholar 

  • Bodkin, J. A., Lasser, R. A., Wines, J. D., Gardner, D. M., and Baldessarini, R. J. (1997). Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J. Clin. Psychiatry 58:137–145.

    PubMed  CAS  Google Scholar 

  • Bond, W. S. (1987). Recognition and treatment of attention deficit disorder. Clin Pharm. 6:617–624.

    PubMed  CAS  Google Scholar 

  • Briley, M. (2004). Clinical experience with dual action antidepressants in different chronic pain syndromes. Hum. Psychopharmacol. 19(Suppl. 1):S21–S25.

    Article  PubMed  CAS  Google Scholar 

  • Brunello, N., Perez, J., Tinelli, D., Rovescalli, A. C., and Racagni, G. (1990). Biochemical and molecular changes in rat cerebral cortex after chronic antidepressant treatment: ‘In vitro’ and ‘in vivo’ studies. Pharmacol. Toxicol. 66(Suppl. 3):112–120.

    Article  PubMed  CAS  Google Scholar 

  • Bymaster, F. P., Katner, J. S., Nelson, D. L., Hemrick-Luecke, S. K., Threlkeld, P. G., Heiligenstein, J. H., Morin, S. M., Gehlert, D. R., and Perry, K. W. (2002). Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711.

    Article  PubMed  CAS  Google Scholar 

  • Carlsson, A., Fuxe, K., and Ungerstedt, U. (1968). The effect of imipramine on central 5-hydroxytryptamine neurons. J. Pharm. Pharmacol. 20:150–151.

    PubMed  CAS  Google Scholar 

  • Carter, G. T., and Sullivan, M. D. (2002). Antidepressants in pain management. Curr. Opin. Investig. Drugs 3:454–458.

    PubMed  CAS  Google Scholar 

  • Christman, A. K., Fermo, J. D., and Markowitz, J. S. (2004). Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder. Pharmacotherapy 24:1020–1036.

    Article  PubMed  CAS  Google Scholar 

  • Coppen, A. (1967). The biochemistry of affective disorders. Brit. J. Psychiatry 113:1237–1264.

    Article  CAS  Google Scholar 

  • Danish University Antidepressant Group (1990). Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker efficacy than clomipramine in a controlled multicenter study. J. Affect. Dis. 18:289–299.

    Article  Google Scholar 

  • D’Aquilla, P. S., Collu, M., Gessa, G. L., and Serra, G. (2000). The role of dopamine in the mechanism of action of antidepressant drugs. Eur. J. Pharmacol. 405:365–373.

    Article  Google Scholar 

  • Eshleman, A. J., Henningsen, R. A., Neve, K. A., and Janowsky, A. (1994). Release of dopamine via the human transporter. Mol. Pharmacol. 45:312–316.

    PubMed  CAS  Google Scholar 

  • Eshleman, A. J., Neve, R. L., Janowsky, A., and Neve, K. A. (1995). Characterization of a recombinant human dopamine transporter in multiple cell lines. J. Pharmacol. Exp. Ther. 274:276–283.

    PubMed  CAS  Google Scholar 

  • Eshleman, A. J., Wolfrum, K., Mash, D. C., Christensen, K., and Janowsky, A. (2001). Drug interactions with the dopamine transporter in cryopreserved human caudate. J. Pharmacol. Exp. Ther. 296:442–449.

    PubMed  CAS  Google Scholar 

  • Fava, M. (2001). Augmentation and combination strategies in treatment-resistant depression. J. Clin. Psychiatry 62:4–11.

    PubMed  CAS  Google Scholar 

  • Galli, A., DeFelice, L. J., Duke, B-D., Moore, K. R., and Blakely, R. D. (1995). Sodium-dependent norepinephrine-induced currents in norepinephrine-transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. J. Exp. Biol. 198:2197–2212.

    PubMed  CAS  Google Scholar 

  • Garris, P. A., Budygin, E. A., Phillips, P. E., Venton, B. J., Robinson, D. L., Bergstrom, B. P., Rebec, G. V., and Wightman, R. M. (2003). A role for presynaptic mechanisms in the actions of nomifensine and haloperidol. Neuroscience 118:819–29.

    Article  PubMed  CAS  Google Scholar 

  • Glowinski, J., and Axelrod, J. (1965). Effect of drugs on the uptake, release and metabolism of 3H-norepinephrine in the rat brain. J. Pharmacol. Exp. Ther. 149:43–49.

    PubMed  CAS  Google Scholar 

  • Inoue, T., Tsuchiya, K., Miura, J., Sakakibara, S., Denda, K., Kasahara, T., and Koyama, T. (1996). Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression. Biol Psychiatry 40:151–153.

    Article  PubMed  CAS  Google Scholar 

  • Kalsner, S. (2000). The question of feedback at the somatodendritic region and antidepressant drug action. Brain Res. Bull. 52:467–473.

    Article  PubMed  CAS  Google Scholar 

  • Leonard, B. E. (1975). Neurochemical and neuropharmacological aspects of depression. Int. Rev. Neurobiol. 18:357–387.

    Article  PubMed  CAS  Google Scholar 

  • Moron, J. A., Brockington, A., Wise, R. A., Rocha, B. A., and Hope, B. T. (2002). Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-in mouse lines. J. Neurosci. 22:389–395.

    PubMed  CAS  Google Scholar 

  • Parini, S., Renoldi, G., Battaglia, A., and Invernizzi, R. W. (2005). Chronic reboxetine desensitizes terminal but not somatodendritic alpha2-adrenoceptors controlling noradrenaline release in the rat dorsal hippocampus. Neuropsychopharmacology 30:1048–1055.

    Article  PubMed  CAS  Google Scholar 

  • Paul, I. A. (2001). Excitatory amino acid signaling, major depression and the actions of antidepressants. Pharm. News 8:33–44.

    CAS  Google Scholar 

  • Paul, I. A., and Skolnick, P. (2003). Glutamate and depression: Clinical and preclinical studies. Ann. New York Acad. Sci. 1003:250–272.

    Article  CAS  Google Scholar 

  • Paul, I. A., Trullas, R., Skolnick, P., and Nowak, G. (1992). Down-regulation of cortical β-adrenoceptors by chronic treatment with functional NMDA antagonists. Psychopharmacology 106:285–287.

    PubMed  CAS  Google Scholar 

  • Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates. Academic Press, New York.

  • Porsolt, R. D., Anton, G., Blavet, N., and Jalfre, M. (1978). Behavioural despair in rats: A new model sensitive to antidepressant treatments. Eur. J. Pharmacol. 47:379–391.

    Article  PubMed  CAS  Google Scholar 

  • Povlock, S. L., and Amara, S. G. (1997). The structure and function of norepinephrine, dopamine and serotonin transporters. In Reith, M. E. A. (ed.), Neurotransmitter Transporters: Structure, Function, and Regulation. Humana Press, Totowa, pp. 1–28.

    Google Scholar 

  • Ramamoorthy, S., Bauman, A. L., Moore, K. R., Han, H., Yang-Feng, T., Chang, A. S., Ganapathy, V., and Blakely, R. D. (1993). Antidepressant- and cocaine-sensitive human serotonin transporter: Molecular cloning, expression, and chromosomal localization. Proc. Natl. Acad. Sci. U.S.A. 90:2542–2546.

    Article  PubMed  CAS  Google Scholar 

  • Randrup, A., Munkvad, J., Fog, R., Gerlach, J., Molander, L., Kjellberg, B., and Scheel-Kruger, J. (1975). Mania, depression and brain dopamine. In Essman, W. B., and Valzelli, L. (eds.), Current Developments in Psychopharmacology, vol. 2. Spectrum Publications, New York, pp. 206–248.

  • Romero, L., Casanovas, J. M., Hervas, I., Cortes, R., and Artigas, F. (1997). Strategies to optimize the antidepressant action of selective serotonin reuptake inhibitors. In Skolnick, P. (ed.), Antidepressants: New Pharmacological Strategies. Humana Press, Totowa, pp. 1–34.

    Google Scholar 

  • Schatzberg, A. F. (2000). New indications for antidepressants. J. Clin. Psychiatry 61(Suppl. 11):9–17.

    PubMed  CAS  Google Scholar 

  • Skolnick, P. (1999). Antidepressants for the new millennium. Eur. J. Pharmacol. 375:31–40.

    Article  PubMed  CAS  Google Scholar 

  • Skolnick, P. (2002) Beyond monoamine-based therapies: Clues to new approaches. J. Clin. Psychiatry 63(Suppl. 2):19–23.

    PubMed  CAS  Google Scholar 

  • Skolnick, P. (2005). Dopamine and depression. In Schmidt, W. (ed.), Dopamine and Glutamate in Psychiatric Disorders, Chapter 9. Humana Press, Totowa, pp. 199–214.

    Google Scholar 

  • Skolnick, P., Legutko, B., Li, X., and Bymaster, F. P.(2001). Current perspectives on the development of non-biogenic amine-based antidepressants. Pharmacol. Res. 43:411–423.

    Article  PubMed  CAS  Google Scholar 

  • Skolnick, P., Popik, P., Janowsky, A., Beer, B., and Lippa, A. S. (2003a). Antidepressant-like actions of DOV 21,947: A “triple” reuptake inhibitor. Eur. J. Pharmacol. 461:99–104.

    Article  PubMed  CAS  Google Scholar 

  • Skolnick, P., Popik, P., Janowsky, A., Beer, B., and Lippa, A. S. (2003b). “Broad spectrum” antidepressants: is more better for the treatment of depression? Life Sci. 73:3175–3179.

    Article  PubMed  CAS  Google Scholar 

  • Tanda, G., Pontieri, F. E., Frau, R., and Di Chiara, G. (1997). Contribution of blockade of the noradrenaline carrier to the increase of extracellular dopamine in the rat prefrontal cortex by amphetamine and cocaine. Eur. J. Neurosci. 9:2077–2085.

    Article  PubMed  CAS  Google Scholar 

  • Willner, P. (2000). Dopaminergic mechanisms in depression and mania. In Watson, S. (ed.), Psychopharmacology: The Fourth Generation of Progress, Online Edition. Lippincott Williams & Wilkins, New York.

    Google Scholar 

  • Zajecka, J. M., and Albano, D. (2004). SNRIs in the management of acute major depressive disorder. J. Clin. Psychiatry 65(Suppl. 17):11–18.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Behavioral Neuroscience Laboratory, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Krakow, Poland

    Piotr Popik & Martyna Krawczyk

  2. Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Krakow, Poland

    Krystyna Golembiowska

  3. Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Krakow, Poland

    Gabriel Nowak

  4. Department of Cytobiology and Histochemistry, Collegium Medicum, Jagiellonian University, 9 Medyczna St., Krakow, Poland

    Gabriel Nowak

  5. VA Medical Center and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health Science University, 3710 SW US Veterans Hospital Rd., Portland, Oregon, USA

    Aaron Janowsky

  6. DOV Pharmaceutical Inc., 433 Hackensack Ave., Hackensack, New Jersey, 07601, USA

    Phil Skolnick, Arnold Lippa & Anthony S. Basile

Authors
  1. Piotr Popik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martyna Krawczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Krystyna Golembiowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriel Nowak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aaron Janowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Phil Skolnick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arnold Lippa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anthony S. Basile
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony S. Basile.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Popik, P., Krawczyk, M., Golembiowska, K. et al. Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677. Cell Mol Neurobiol 26, 855–871 (2006). https://doi.org/10.1007/s10571-006-9012-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-006-9012-5

KEY WORDS:

Search

Navigation