尿素通道是特异性通透尿素的跨膜蛋白，在肾脏尿浓缩机制中发挥重要作用。前期工作发现尿素通道功能性敲除可导致尿素选择性利尿，且不引起钠、钾、氯离子丢失和蓄积。因此，我们提出“尿素通道蛋白可作为新的利尿药作用靶点，其抑制剂可研发成为新型利尿药”的科学假说，其优势在于“利尿作用不影响机体电解质平衡”。本项目拟在发现活性化合物优替作为尿素通道抑制剂，在体内具有尿素选择性利尿作用,并不引起血钠、钾、氯水平改变的前期工作基础上，利用药物设计的基本原理对先导化合物优替进行结构优化；通过研究尿素通道蛋白与优替复合物的三维结构，借助于计算机虚拟分子对接技术发现新结构类型的利尿药；利用尿素通道蛋白基因定点突变、化合物药理学评价等技术，研究活性化合物在尿素通道蛋白上的作用位点和作用机理。本研究的目标是确定尿素通道蛋白作为新型利尿药作用靶点的可行性，获得药理学特性优良的新型利尿药先导化合物。

Urea transporters are a group of membrane proteins that are specifically permeable to urea. They mediate the intrarenal urea recycling to play an important role in urine concentration. Previous work showed that knockout of urea transporters resulted in urea-related urine concentration defect, but did not affect electrolyte balance. Therefore, we propose that urea transporters may act as new diuretic drug targets, and that urea transporter inhibitors can be used as new diuretics. These new diuretics would not cause electrolyte disturbance. Our previous work showed that a new urea transporter inhibitor PU-14 had significant diuretic effect without affecting blood Na+, K+ and Cl- concentrations. Based on the crystal structure of a urea transporter (UT-B) and the chemical characteristics of active compounds, this project aims to determine the active sites and mechanism of active compounds interacting with urea transporters using structure-activity relationship analysis, molecular docking, site-directed mutagenesis, chemical structure modification, complex crystal structure determination and three-dimensional structure directed rational drug design. The purpose of this study is to determine the feasibility of urea transporters as novel diuretic drug targets and to discover lead compounds of novel diuretics with excellent pharmacological characteristics.