title: Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters.
abstract: 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 μM. 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Huiwen
authors.initials: H
authors.lastname: Ren
authors.affiliation: Renal Division, Departments of Medicine and Physiology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Yongning
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Anatomy, Neuroscience Research Center, Basic Medical College, Chongqing Medical University, Chongqing, China; and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ran
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Tianluo
authors.initials: T
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China;
authors.forename: Runtao
authors.initials: R
authors.lastname: Li
authors.affiliation: Renal Division, Departments of Medicine and Physiology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China baoxue@bjmu.edu.cn.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D001692:Biological Transport; D015415:Biomarkers / Q000097:blood; D002712:Chlorides / Q000097:blood; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D007671:Kidney Concentrating Ability / Q000187:drug effects; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009994:Osmolar Concentration; D011188:Potassium / Q000097:blood; D020033:Protein Isoforms; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000097:blood; D013329:Structure-Activity Relationship; D013997:Time Factors; D014508:Urea / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002712:Chlorides; D004232:Diuretics; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D011804:Quinolines; C452857:urea transporter B, mouse; D014508:Urea; D012964:Sodium; D011188:Potassium
keywords: diuretics; drug discovery; drug target; urine concentrating mechanism; vasopressin