Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

Aloke K Dutta,Chandrashekhar Voshavar,Tamara Antonio,Maarten E A Reith,Soumava Santra,Liping Xu,Omar Mabrouk,Horrick Sharma,Vinod K Yaragudri

doi:10.1371/journal.pone.0113420

Aloke K Dutta, Chandrashekhar Voshavar + Show 7 more

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https://doi.org/10.1371/journal.pone.0113420

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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.

Highlights

Major depressive disorder is a debilitating illness affecting 15–20% of the population in the United States [1]
D-473 was characterized in cells expressing cloned human transporters (Table 1, Figure 3)
Patients with melancholic symptoms experience loss of appetite and weight loss, insomnia and psychomotor agitation as well as less responsive to environmental stimuli whereas atypical depression is associated with an increased appetite, weight gain, fatigue, hypersomnia and psychomotor retardation [35, 36]

Summary

Introduction

Major depressive disorder is a debilitating illness affecting 15–20% of the population in the United States [1]. There still remains a significant unmet need for much more improved therapy, as large numbers of depressed people, an estimated 15–30%, are still refractory to the current existing therapies. The medial prefrontal cortex brain area has been shown to be associated with depressed mood and sadness and neuroimaging studies indicated certain deficiencies of neuronal activities in this area with depressed subjects [6]. This region receives innervation from all three monoamines, restoration in the imbalanced level of monoamines by antidepressants has been shown to improve symptoms of depression [7].

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