Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters

Abstract

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

Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template

“…[44, 45] Recently, we have reported development of an orally active TRI, D-473 (Figure 1), which exhibited efficacious activity in FST and elevated level of all three monoamines in a microdialysis study. 46 …”

Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice

“…More recently, it was found that depressed patients had greater DAT expression on both sides of the striatum and that bupropion's treatment reduced significantly DAT binding in the striatum [82]. Also, the triple reuptake inhibitors JZAD-IV-22, TP1, and D-473 that block the dopamine, norepinephrine, and serotonin transporters exhibited antidepressant-like efficacy in the FST and/or TST without locomotor stimulant or sensitization properties [83][84][85]. However, deep brain stimulation of the medial forebrain bundle in male Wistar rats showed a significant increase in swimming duration, that was associated to a significant increase in DAT protein expression in the hippocampus [86].…”

Novel Potent Dopamine–Norepinephrine and Triple Reuptake Uptake Inhibitors Based on Asymmetric Pyran Template and Their Molecular Interactions with Monoamine Transporters

“…In our recent work, we demonstrated successful development of orally active TRIs which exhibited high efficacy in the rat animal model of depression. 28,29 Furthermore, we have recently shown that the novel TRI D-578 exhibits greater efficacy than that of paroxetine in normalizing traumatic-stress-induced extinction learning in the single prolonged stress (SPS) rat model of PTSD. 28 D-578 also produces robust and efficacious antidepressant effects in the forced swim test without confounding locomotor effects.…”

“…21,24−27 Two orally active lead TRIs, D-473 and D-578 (Figure 1), exhibited high efficacy in the depression and PTSD animal models. 28,29 In this regard, these compounds were more efficacious than the reference drugs. In another line of experiments, we developed a number of potent DNRI-type compounds which gave us an indication for the structural requirement for such an activity in pyran derivatives.…”