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  • Title: Antidiarrheal efficacy of a quinazolin CFTR inhibitor on human intestinal epithelial cell and in mouse model of cholera.
    Author: Patanayindee J, Muanprasat C, Soodvilai S, Chatsudthipong V.
    Journal: Indian J Pharmacol; 2012; 44(5):619-23. PubMed ID: 23112425.
    Abstract:
    OBJECTIVE: This study aimed to evaluate the antidiarrheal efficacy and pharmacological properties of ethyl 2-(4-oxo-3-o-tolyl-3,4-dihydroquinazolin-2-ylthio)acetate (DQA) as an inhibitor of cystic fibrosis transmembrane conductance regulator protein (CFTR) both in vitro and in vivo. MATERIALS AND METHODS: The effects of DQA on CFTR function and cell viability were investigated in Fisher rat thyroid (FRT) cells expressing human CFTR and human intestinal epithelial T84 cells by short-circuit current measurements and MTT assays, respectively. In vivo antidiarrheal efficacy of DQA was evaluated in a closed loop model of cholera in mice. RESULTS: In permeabilized FRT cells, apical chloride current induced by CFTR agonists (10 μM forskolin, 100 μM CPT-cAMP, and 20 μM apigenin) was inhibited by DQA with IC(50) ~ 20 μM and complete inhibition at 200 μM. The inhibitory effect was reversible and not associated with cytotoxicity to FRT cells (5-500 μM DQA for 24 h). Likewise, DQA effectively inhibited both forskolin and cholera toxin-induced transepithelial chloride secretion in T84 cells. In mice, intraluminal injection of 100 μM DQA reduced cholera toxin (1 μg/closed loop)-induced intestinal fluid secretion by 85% without affecting intestinal fluid absorption. CONCLUSIONS: DQA represents a new class of small molecule CFTR inhibitor with potential application in treatment of cholera.
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