Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters
Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters
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DOI：
10.1371/journal.pone.0113420
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发表时间：
2014-11-26
期刊：
影响因子：
3.7
通讯作者：
Reith, Maarten E. A.
中科院分区：
文献类型：
--
作者：
Dutta, Aloke K.;Santra, Soumava;Reith, Maarten E. A.
重性抑郁症（MDD）是一种使人衰弱的疾病，影响着世界各地广泛的人群。目前的抑郁症治疗是不够的，有一个相当大的未满足的需要，更有效的治疗。多巴胺已被证明在抑郁症中起重要作用，包括产生快感缺乏，这是MDD中未经治疗的症状之一。据推测，作用于所有三种单胺转运蛋白（包括多巴胺转运蛋白）的药物应提供更有效的抗抑郁活性。这导致了三重再摄取抑制剂D-473的开发，D-473是一种基于吡喃的新型分子，与所有三种单胺转运蛋白相互作用。在HEK-293细胞中表达的克隆人转运蛋白中的单胺摄取抑制活性（DAT、SERT和NET分别为70.4、9.18和39.7）表明该药物具有5-羟色胺偏好的三重再摄取抑制特征。药物D-473具有良好的脑渗透性，口服给药在大鼠强迫游泳试验中产生有效的活性。最佳有效剂量未产生任何自发激活。微透析实验表明，D-473全身给药有效地提高了背外侧纹状体（DLS）和内侧前额叶皮质（mPFC）区细胞外三种单胺DA，5-HT和NE的水平，表明D-473在体内阻断了所有三种单胺转运蛋白。因此，D-473的当前生物学数据表明该分子具有强效抗抑郁活性。
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.