Discovery, characterization, and structure-activity relationships of an inhibitor of inward rectifier potassium (Kir) channels with preference for Kir2.3, Kir3.x, and Kir7.1.
Discovery, characterization, and structure-activity relationships of an inhibitor of inward rectifier potassium (Kir) channels with preference for Kir2.3, Kir3.x, and Kir7.1.
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DOI：
10.3389/fphar.2011.00075
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发表时间：
2011
影响因子：
5.6
通讯作者：
Denton JS
中科院分区：
文献类型：
--
作者：
Raphemot R;Lonergan DF;Nguyen TT;Utley T;Lewis LM;Kadakia R;Weaver CD;Gogliotti R;Hopkins C;Lindsley CW;Denton JS
钾离子向内整流家族（Kir）通道由至少16个家族成员组成，表现出广泛且经常重叠的细胞、组织或器官分布。人类致病突变的发现和基因敲除小鼠的实验，突显了Kir通道在生理学中的重要性，在某些情况下，对它们作为药物靶点的潜力提出了质疑。然而，针对特定家庭成员的有效和选择性小分子调节剂的缺乏，除了少数例外，阻碍了了解其生理学和评估其治疗潜力的努力。越来越多的证据表明，G蛋白偶联内向整流K （GIRK）通道的Kir3。X亚家族可能是房颤治疗的新靶点。为了扩大GIRK的分子药理学，我们对Kir1.1抑制剂库进行了基于铊（Tl+）通量的高通量筛选，以筛选GIRK的调节剂。其中一个名为VU573的化合物对GIRK的选择性是Kir1.1的10倍（IC50分别为1.9 μM和19 μM），因此被选为进一步研究的对象。在非洲爪蟾卵母细胞和哺乳动物细胞的电生理实验中，VU573对Kir3.1/3.2（神经元GIRK）和Kir3.1/3.4（心脏GIRK）通道的抑制作用相同，且对kirk、Kir2.3和Kir7.1的抑制作用优于Kir1.1和Kir2.1。我们建立了Kir2.3和Kir7.1的M125R孔突变体的Tl+通量分析，以支持药物化学研究开发这些通道的更有效和选择性的类似物。VU573的结构-活性关系表明，很少有类似物具有提高的效力，但两个化合物保留了大部分对GIRK和Kir2.3的活性，而失去了对Kir7.1的活性。我们预计VU573系列将有助于探索这些Kir通道的生理和结构-功能关系。
The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels.
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DOI：
10.1073/pnas.1004021107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Caballero, Ricardo;Dolz-Gaiton, Pablo;Delpon, Eva
通讯作者：
Delpon, Eva
影响因子：
3
作者：
Lopez-Izquierdo, Angelica;Ponce-Balbuena, Daniela;Sanchez-Chapula, Jose A.
通讯作者：
Sanchez-Chapula, Jose A.
影响因子：
3.6
作者：
Bhave, Gautam;Chauder, Brian A.;Denton, Jerod S.
通讯作者：
Denton, Jerod S.
影响因子：
2.9
作者：
Jin, WL;Lu, Z
通讯作者：
Lu, Z
影响因子：
2.4
作者：
CAROTI, P;CECCOTTI, C;PRIMOFIORE, G
通讯作者：
PRIMOFIORE, G