Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677

Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. Basile

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)857-873
Number of pages17
JournalCellular and Molecular Neurobiology
Volume26
Issue number4-6
DOIs
StatePublished - Jul 1 2006

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Keywords

  • Antidepressant
  • Dopamine
  • Forced swim test
  • Microdialysis
  • Norepinephrine
  • Prepulse inhibition
  • Serotonin
  • Transporter

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Popik, P., Krawczyk, M., Golembiowska, K., Nowak, G., Janowsky, A., Skolnick, P., Lippa, A., & Basile, A. S. (2006). Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677. Cellular and Molecular Neurobiology, 26(4-6), 857-873. https://doi.org/10.1007/s10571-006-9012-5