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

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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.

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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

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  1. Piotr Popik
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Correspondence to Anthony S. Basile.

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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

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