Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters
Reuptake
Norepinephrine transporter
Serotonin reuptake inhibitor
DOI:
10.1371/journal.pone.0113420
Publication Date:
2014-11-26T20:47:57Z
AUTHORS (8)
ABSTRACT
Major depressive disorder (MDD) is a debilitating disease affecting wide cross section of people around the world. The current therapy for depression less than adequate and there considerable unmet need more efficacious treatment. Dopamine has been shown to play significant role in including production anhedonia which one untreated symptoms MDD. It hypothesized that drugs acting at all three monoamine transporters dopamine transporter should provide antidepressants activity. This led development triple reuptake inhibitor D-473 novel pyran based molecule interacts with transporters. uptake inhibition activity cloned human expressed HEK-293 cells (70.4, 9.18 39.7 DAT, SERT NET, respectively) indicates serotonin preferring profile this drug. drug exhibited good brain penetration produced rat forced swim test under oral administration. optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated systemic administration elevated extracellular level monoamines DA, 5-HT, NE efficaciously dorsal lateral striatum (DLS) medial prefrontal cortex (mPFC) area, indicating vivo blockade by D-473. Thus, biological data from indicate potent antidepressant molecule.
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