A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic
A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic
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一种新型小分子噻吩并喹啉尿素转运蛋白抑制剂可作为潜在的利尿剂。
DOI：
10.1038/ki.2013.62
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发表时间：
2013-06-01
影响因子：
19.6
通讯作者：
Yang, Baoxue
中科院分区：
文献类型：
--
作者：
Li, Fei;Lei, Tianluo;Yang, Baoxue
尿素转运蛋白(UTS)是一类膜通道蛋白家族，对尿素具有特异性的通透性，在肾内尿素循环和尿液浓缩中发挥重要作用。利用红细胞渗透裂解试验，我们筛选了一个小分子文库，以寻找UT促进的尿素转运的抑制剂。鉴定了一类新的硫代喹啉UT-B抑制剂，其中PU-14对人、兔、大鼠和小鼠的UT-B具有较强的抑制活性。PU-14对大鼠UT-B介导的尿素转运的半数抑制浓度为∼0.8μ/L，对缺乏UT-B的小鼠红细胞的尿素转运无明显影响，但对UT-A型尿素转运体有36%的抑制作用，在4μ/L时抑制率为36%。PU-14在80μ摩尔/L的浓度下无明显的细胞毒性。提示PU-14具有尿素选择性利尿作用。因此，PU-14或其类似物可能被开发为一种新的利尿剂，在不引起电解质失衡的情况下，在与水滞相关的疾病中增加肾脏液体的清除。PU-14可以建立化学基因敲除的动物模型来研究UTS的生理功能。
Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small-molecule library for inhibitors of UT-facilitated urea transport. A novel class of thienoquinolin UT-B inhibitors were identified, of which PU-14 had potent inhibition activity on human, rabbit, rat, and mouse UT-B. The half-maximal inhibitory concentration of PU-14 on rat UT-B-mediated urea transport was ∼0.8 μmol/l, and it did not affect urea transport in mouse erythrocytes lacking UT-B but inhibited UT-A-type urea transporters, with 36% inhibition at 4 μmol/l. PU-14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 μmol/l. Subcutaneous delivery of PU-14 (at 12.5, 50, and 100 mg/kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU-14 has a diuretic effect by urea-selective diuresis. Thus, PU-14 or its analogs might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance. PU-14 may establish ‘chemical knockout’ animal models to study the physiological functions of UTs.