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Targeting the Kv11.1 (hERG) channel with allosteric modulators. Synthesis and biological evaluation of three novel series of LUF7346 derivatives
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-11-21 , DOI: 10.1016/j.ejmech.2020.113033
Jacobus P.D. van Veldhoven , Giulia Campostrini , Constantijn J.E. van Gessel , Dorien Ward-van Oostwaard , Rongfang Liu , Christine L. Mummery , Milena Bellin , Adriaan P. IJzerman

We synthesized and evaluated three novel series of substituted benzophenones for their allosteric modulation of the human Kv11.1 (hERG) channel. We compared their effects with reference compound LUF7346 previously shown to shorten the action potential of cardiomyocytes derived from human stem cells. Most compounds behaved as negative allosteric modulators (NAMs) of [3H]dofetilide binding to the channel. Compound 9i was the most potent NAM amongst all ligands, remarkably reducing the affinity of dofetilide in competitive displacement assays. One of the other derivatives (6k) tested in a second radioligand binding set-up, displayed unusual displacement characteristics with a pseudo-Hill coefficient significantly distinct from unity, further indicative of its allosteric effects on the channel. Some compounds were evaluated in a more physiologically relevant setting in beating cardiomyocytes derived from human induced pluripotent stem cells. Surprisingly, the tested compounds showed effects quite different from the reference NAM LUF7346. For instance, compound 5e prolonged, rather than shortened, the field potential duration, while it did not influence this parameter when the field potential was already prolonged by dofetilide. In subsequent patch clamp studies on HEK293 cells expressing the hERG channel the compounds behaved as channel blockers. In conclusion, we successfully synthesized and identified new allosteric modulators of the hERG channel. Unexpectedly, their effects differed from the reference compound in functional assays on hERG-HEK293 cells and human cardiomyocytes, to the extent that the compounds behaved as channel blockers in their own right.



中文翻译:

使用变构调节剂定位K v 11.1(hERG)通道。三种新型LUF7346衍生物的合成及生物学评价

我们合成和评估了三个新系列的取代的二苯甲酮对人类K v 11.1(hERG)通道的变构调节。我们将它们的作用与参考化合物LUF7346进行了比较,该化合物先前已显示出可缩短源自人干细胞的心肌细胞的动作电位。大多数化合物表现为[ 3 H] dofetilide与通道结合的负变构调节剂(NAM)。在所有配体中,化合物9i是最有效的NAM,在竞争性置换分析中明显降低了多非利特的亲和力。其他衍生工具之一(6k)在第二个放射性配体结合设置中进行测试,显示出异常的位移特征,其假山系数明显不同于单位,进一步表明了其对通道的变构作用。在源自人诱导的多能干细胞的跳动心肌细胞中,在更生理相关的环境中评估了某些化合物。出人意料的是,测试的化合物显示出与参考NAM LUF7346完全不同的效果。例如,化合物5e延长而不是缩短了场电势的持续时间,而当多芬替利已经延长了场电势时,它不影响该参数。在随后的表达hERG通道的HEK293细胞的膜片钳研究中,这些化合物起通道阻滞剂的作用。总之,我们成功合成并鉴定了hERG通道的新变构调节剂。出乎意料的是,在对hERG-HEK293细胞和人心肌细胞的功能测定中,它们的作用不同于参考化合物,其程度在于该化合物本身具有通道阻断剂的作用。

更新日期:2020-11-22
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