Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram,RSC Medicinal Chemistry

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Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-6-9 , DOI: 10.1039/d1md00072a
Gisela Andrea Camacho-Hernandez ₁ , Andrea Casiraghi _{1,

2} , Deborah Rudin ₃ , Dino Luethi _{3,

4} , Therese C Ku ₁ , Daryl A Guthrie ₁ , Valentina Straniero ₂ , Ermanno Valoti ₂ , Gerhard J Schütz ₄ , Harald H Sitte ₃ , Amy Hauck Newman ₁

Affiliation

The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe 6 demonstrated high binding affinity (K_i = 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT; K_i = 1540 nM) and serotonin (SERT; K_i = 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound 6 was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.

中文翻译：

照亮去甲肾上腺素转运蛋白：基于尼索西汀和他普仑的荧光探针

利用荧光配体研究单胺转运蛋白 (MAT) 增加了我们对它们在活细胞系统中的功能和分布的了解。在这项研究中，我们将尼索西汀和他普仑的 SAR 扩展为母体化合物，以确定去甲肾上腺素转运蛋白 (NET) 的高亲和力罗丹明标记荧光探针。基于尼索西汀的荧光探针6对 NET表现出高结合亲和力 ( K _i = 43 nM)，与多巴胺 (DAT; K _i = 1540 nM) 和血清素 (SERT; K _i = 785 nM)的其他转运蛋白相比，总体选择性在竞争性放射性配体结合测定中。使用共聚焦显微镜，化合物6显示在表达转运蛋白的细胞中在低纳摩尔浓度下染色 NET 和 SERT，但不染色 DAT。

更新日期：2021-06-09

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