Identification of New Small Molecule Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Protein : In Vitro and in Vivo Studies(Pharmacology)

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概要

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• Cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated chloride channel that has been proposed as a pharmacological target to reduce intestinal fluid loss in cholera. The aim of this study was to identify new CFTR inhibitors by high-throughput screening. Screening of 50,000 drug-like small molecules was performed using a cell-based assay of iodide influx in Fisher rat thyroid (FRT) cells co-expressing human CFTR and halide-sensitive yellow fluorescent protein (YFP-H148Q). Two new CFTR inhibitors, 2-[N-(3-hydroxy-4-carboxyphenyl) amino]-4-(4-methylphenyl)-thiazole (INH 1) and 1-acetyl-5-bromo-2,3-dihydro-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-Indole-7-sulfonamide (INH 2), were identified. They were then determined for potency, reversibility and specificity by electrophysiological methods, and for in vivo efficacy in mouse model of cholera toxin-induced intestinal fiuid secretion. INH 1 and INH 2 reversibly inhibited cAMP-activated apical chloride current in FRT cells with K_is of 15 and 20μM, respectively, Similarly, in short-circuit current analysis in human colonic epithelial cell lines (T84 cells), cAMP-activated chloride secretion was inhibited by INH 1 and INH 2 with K_iS of 24.5 and 25.3 μM, respectively. Calcium-activated chloride secretion in the T84 cells was markedly inhibited by 100 μM of INH 1, but was unaffected by 100 μM of INH 2. In vivo studies in mice showed that a single intraperitoneal injection of INH 1 (3 mg/kg) reduced cholera toxin-induced intestinal fluid secretion by 40%, whereas INH 2 produced no effect. Our results indicate that INH 1 could be a new class candidate for a blocker of cholera toxin-induced intestinal fiuid secretion as well as a CFTR inhibitor.

• 2007-03-01

著者

• Kaewmokul Santi

  Department Of Physiology Faculty Of Science Mahidol University

• MUANPRASAT Chatchai

  Department of Physiology, Faculty of Science, Mahidol University

• CHATSUDTHIPONG Varanuj

  Department of Physiology, Faculty of Science, Mahidol University

• Muanprasat Chatchai

  Department Of Physiology Faculty Of Science Mahidol University

• Chatsudthipong Varanuj

  Dep. Of Physiology Fac. Of Sci. Mahidol Univ.

• Chatsudthipong Varanuj

  Department Of Physiology Mahidol University

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