Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A
Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A
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DOI：
10.1096/fj.201900858r
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发表时间：
2019-10-01
期刊：
影响因子：
4.8
通讯作者：
Verkman, Alan S.
中科院分区：
文献类型：
--
作者：
Cil, Onur;Anderson, Marc O.;Verkman, Alan S.
Cajal间质细胞表达钙活化的氯离子通道跨膜成员16A (TMEM16A)，是胃肠运动的重要决定因素。我们之前鉴定了酰基氨基环烷基噻吩类TMEM16A抑制剂，根据药物化学，它们产生类似于2-溴代氟乙酰氨基-5,6,7,8-四氢- 4h -环庚[b]噻吩-3-羧酸邻甲基酰胺（TMinh-23），具有30 nM的半最大抑制浓度。在这里，我们测试了TMinh-23对小鼠胃肠道运动的抑制作用。在离体小鼠胃窦，TMinh-23强烈抑制自发和碳水化合物刺激的节律性收缩。药代动力学分析显示，单次口服或腹腔注射10mg /kg剂量后，TMinh-23的治疗浓度至少可维持4小时。胃排空，在口服酚红或单独通过[Tc-99m]-二乙烯三胺五乙酸显像评估后，在20分钟内，TMinh-23减少了60%。有趣的是，TMinh-23对基线全肠转运时间或蓖麻油致腹泻时间几乎没有影响。由于胃排空延迟，TMinh-23给药显著降低了小鼠口服而非腹腔葡萄糖负荷后的血糖升高。这些结果为TMEM16A参与胃排空提供了药理学证据，并提示TMEM16A抑制在胃排空加速紊乱（如倾倒综合征）中的应用，并可能改善糖尿病/代谢综合征的糖耐量和肥胖症的饱腹感。-Cil， O, Anderson， M. O, Yen， R, Kelleher， B., Huynh， T. L., Seo， Y., Nilsen， S. P, Turner， J. R, Verkman, a . S.钙活化氯通道TMEM16A纳米分子效价抑制剂减缓胃排空和改善口服葡萄糖耐量。
Interstitial cells of Cajal, which express the calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide (TMinh-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TMinh-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh-23 strongly inhibited spontaneous and carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh-23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [Tc-99m]-diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh-23 by similar to 60% at 20 min. Interestingly, there was little effect of TMinh-23 on baseline whole-gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TMinh-23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.-Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.