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Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2018-05-23 , DOI: 10.1016/j.ejmech.2018.05.032
David Schaller , Miyase Gözde Gündüz , Fang Xiong Zhang , Gerald W. Zamponi , Gerhard Wolber

Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.



中文翻译:

结合机制研究指导具有L- / T型钙通道阻滞活性的新型稠合1,4-二氢吡啶衍生物的合成

硝苯地平和异拉地平是带有1,4-二氢吡啶(DHP)支架的钙通道阻滞剂的主要实例。尽管数十年来已成功地在临床上用于治疗高血压,但对其靶标L型电压门控钙通道Cav1.2的结合机制仍未完全了解。最近,发现了具有稠环系统的新型DHP衍生物,它们对不同的钙通道亚型表现出不同的选择性。此特性使DHP类成为实现对不同钙通道亚型选择性的有前途的工具。在这项研究中,我们使用对接和药效团分析方法确定了著名的DHP硝苯地平和异拉地平的常见结合模式,该模式也可以解释小亚基DHP衍生物与稠环系统的构效关系。这些发现被用来指导22种新型DHP的合成。广泛的表征使用1 H NMR,13 C NMR,质谱和元素分析之后是全细胞膜片钳测定法,用于分析在Cav1.2和Cav3.2处的活性。鉴定出两种化合物具有针对Cav1.2的显着活性。此外,我们鉴定了对Cav3.2有活性的四种化合物,其中三种对Cav1.2具有选择性。使用对接和药效团分析以及分子动力学模拟来分析新型结合模式。

更新日期:2018-05-23
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