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A Novel Small‐molecule Urea Transporter Inhibitor Acts as a Potential Diuretic
Author(s) -
Yang Baoxue,
Li Fei,
Lei Tianluo,
Zhou Hong
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1111.1
Subject(s) - urea , chemistry , diuretic , pharmacology , transporter , ic50 , biochemistry , in vitro , biology , gene
Urea transporters (UT) are a family of membrane channel proteins that are specifically permeable to urea. They play an important role in intrarenal urea recycling and in urinary concentrating mechanism. Using an erythrocyte osmotic lysis assay, we screened a small molecule library for inhibitors of UT‐facilitated urea transport. A novel class of UT‐B inhibitors were identified, named as thienoquinolin,one of which, PU‐14, had potent inhibition activity on human, rabbit, rat and mouse UT‐B. IC50 of PU‐14 on rat UT‐B mediated urea transport was about 0.8 μM. PU‐14 did not affect urea transport in mouse erythrocytes lacking UT‐B. PU‐14 also inhibited UT‐A‐type urea transporters, with 36 % inhibition at 4 μM. PU‐14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 μM. 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 osmolalities without electrolyte disturbances and liver and renal damages, which suggests that PU‐14 has a diuretic effect by urea‐selective diuresis. These results indicate that PU‐14 or its analogues might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance, as well as a tool drug to establish ‘chemical knockout□ animal models to study the physiological functions of UTs.