Institute of Pharmacology, Medical University, Vienna, Austria.
Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.
Neuropharmacology. 2019 Dec 15;161:107615. doi: 10.1016/j.neuropharm.2019.04.021. Epub 2019 Apr 24.
The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (pCFMCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the pCFgroup, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that pCFMCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
多巴胺（DAT）和 5-羟色胺（SERT）转运体是治疗精神疾病（包括重度抑郁症、焦虑症和注意缺陷多动障碍）的重要靶点。作用于这些转运体的药物可以作为抑制剂或释放剂。此外，最近人们认识到，一些化合物作为安非他命的释放剂效果较差。因此，它们被归类为部分释放剂。化合物可以作用于 SERT 和 DAT，也可以对 SERT 或 DAT 显示出精细的选择性，但选择性的结构基础理解得很差。已证明，在间位用三氟甲基取代甲卡西酮，可使甲卡西酮（MCAT）对 SERT 的选择性显著提高。在这里，我们研究了 MCAT、间位三氟甲基甲卡西酮（pCFMCAT）和其他类似物，以了解（i）选择性的决定因素和（ii）MCAT 间位 CF 取代对转运周期的影响。我们通过生化、计算和电生理方法系统地测试了不同的间位取代的 MCAT：加入 pCF 基团，但不是其他具有较大范德华体积、亲脂性或极性的取代基，将 DAT 选择性的 MCAT 转化为 SERT 选择性的部分释放剂。电生理和灌注实验，以及动力学建模表明，pCFMCAT，而不是 MCAT，通过占据 S2 位将一部分 SERT 固定在无活性状态。这些发现定义了部分释放剂的一种新作用机制，与部分释放的其他两种已知结合模式不同。我们的观察结果强调了一个事实，即单胺转运体的底物渗透途径支持多种结合模式，可用于药物设计。本文是题为“神经递质转运体特刊”的一部分。
