title: A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Tianluo
authors.initials: T
authors.lastname: Lei
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhu
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Jihui
authors.initials: J
authors.lastname: Chen
authors.forename: Zixun
authors.initials: Z
authors.lastname: Dong
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014508:Urea / Q000378:metabolism*; D014554:Urination / Q000187:drug effects; D014882:Water-Electrolyte Balance / Q000187:drug effects; D000096982:Urea Transporters
chemical_list: D004232:Diuretics; D026901:Membrane Transport Proteins; D011804:Quinolines; D014508:Urea; D000096982:Urea Transporters