Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters
Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters
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噻吩并喹啉类通过强烈抑制 UT-A 尿素转运蛋白发挥利尿作用
DOI：
10.1152/ajprenal.00421.2014
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发表时间：
2014-12-15
影响因子：
4.2
通讯作者：
Yang, Baoxue
中科院分区：
文献类型：
--
作者：
Ren, Huiwen;Wang, Yanhua;Yang, Baoxue
尿素转运蛋白（UT）通过介导肾内尿素再循环在尿液浓缩机制中发挥重要作用，表明UT抑制剂可作为一类新型利尿剂具有治疗用途。最近，我们发现了一种噻吩并喹啉UT抑制剂PU-14，具有利尿活性。本研究的目的是确定更有效的UT抑制剂，强烈抑制内髓集合管（IMCD）中的UT-A亚型。通过构效关系分析，筛选出了有效的噻吩并喹啉类UT抑制剂。在灌注的大鼠终末IMCD中测定尿素转运抑制活性。使用代谢笼在大鼠和小鼠中测定化合物的利尿活性。结果表明，化合物PU-48具有较强的UT-A抑制活性。抑制率为69.5%，IC 50为0.32 μ M。PU-48显著抑制灌注大鼠终末IMCD中的尿素转运。PU-48在UT-B缺失小鼠中引起显著的利尿，这表明UT-A是PU-48的靶标。PU-48引起的利尿作用未改变大鼠和小鼠的血液Na+、K+或Cl-水平或非尿素溶质排泄。在用PU-48处理的细胞或动物中未检测到毒性。结果表明，噻吩并喹啉UT抑制剂通过抑制IMCD中的UT-A来诱导利尿。这表明它们可能有潜力被开发为一类新的利尿剂，其副作用比经典利尿剂少。
Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 mu M. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na+, K+, or Cl- levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics.