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I. Cyclodextrin-based receptors for peptide recognition. II. Molecular determinants of flecainide action on the human cardiac sodium channel.

机译：I.用于肽识别的基于环糊精的受体。二。氟卡尼对人心脏钠通道作用的分子决定因素。

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摘要

Chapter 1. Cyclodextrin-based receptors for peptide recognition . A synthetic approach to cyclodextrin trimers based on semi-rigid scaffolds is described. The synthetic challenges involved in the preparation of these receptors are discussed. The binding properties of the receptors with different L-tryptophan and t-butyl phenylalanine based substrates are explored. Trimeric binding was demonstrated to be stronger than dimeric binding. The thermodynamics of complexation were explored. Cyclodextrin dimers were investigated for their ability to bind natural peptide hormones. A detailed study of the binding of a secondary face, ester linked dimer to α-melanocyte hormone was undertaken. Finally, versatile synthetic routes to cyclodextrin-peptide hybrids are presented. Both stepwise solid phase synthesis and post-synthetic covalent modification methods are discussed. The binding properties of cyclodextrin-peptide hybrids containing two and three β-cyclodextrins are described.; Chapter 2. Molecular determinants of flecainide action on the human cardiac sodium channel. A novel neutral analog of the antiarrhythmic drug flecainide was designed and synthesized. A quaternary analog of flecainide, previously reported but not fully characterized, was synthesized. The effects of these drugs in wild type and mutant human cardiac sodium channels were investigated and compared with flecainide, lidocaine, and quaternary lidocaine (QX-314). The neutral analog was found to shift the steady-state inactivation curve without conditioning pulses and shown to have a high affinity for the inactivated state.{09}The binding to the inactivated state by the neutral analog and lidocaine was disrupted by F1760A and Y1767A mutations. This represents the first direct evidence of flecainide binding to the inactivated state of the channel.; Blocking properties of quaternary flecainide were shown to be similar to quaternary lidocaine. Both drugs exert strong use-dependent block when applied internally but weak block when applied externally. This suggests an intracellular access route for flecainide to its binding site. The quaternary compound, like flecainide, but unlike the neutral analog, does not shift the inactivation curve without conditioning pulses.; These data provide further understanding of the molecular mechanism of flecainide action in cardiac sodium channels and demonstrate the utility of a new molecular tool for the investigation of flecainide action in mutant sodium channels associated with cardiac disease.
机译：第1章。基于环糊精的肽识别受体。描述了一种基于半刚性支架的环糊精三聚体的合成方法。讨论了与这些受体的制备有关的合成挑战。探索了受体与不同的L-色氨酸和 t 丁基苯基丙氨酸的底物的结合特性。已证明三聚体结合比二聚体结合更强。探索了络合的热力学。研究了环糊精二聚体结合天然肽激素的能力。进行了二次研究，酯连接的二聚体与α-黑素细胞激素的结合的详细研究。最后，介绍了通向环糊精-肽杂化物的通用合成途径。讨论了逐步固相合成和合成后的共价修饰方法。描述了含有两个和三个β-环糊精的环糊精-肽杂化物的结合特性。 第2章。氟卡尼对人心脏钠通道的作用的分子决定因素。设计并合成了抗心律不齐药物氟卡尼的新型中性类似物。合成了氟卡尼的季铵盐类似物，先前已报道但尚未完全表征。研究了这些药物在野生型和突变型人类心脏钠通道中的作用，并与氟卡尼，利多卡因和季利多卡因（QX-314）进行了比较。发现中性类似物在没有调节脉冲的情况下移动了稳态灭活曲线，并且显示出对灭活状态具有高度亲和力。{09}中性类似物和利多卡因与灭活状态的结合被F1760A和Y1767A突变破坏了。这是氟卡尼与通道灭活状态结合的第一个直接证据。氟卡尼季铵盐的阻滞性能与利多卡因季铵盐相似。两种药物在内部应用时均表现出强烈的使用依赖性阻滞，而在外部应用时则表现出微弱的依赖依赖性。这表明氟卡尼至其结合位点的细胞内进入途径。与氟卡尼类似的四元化合物，与中性类似物不同，在没有调节脉冲的情况下不会移动失活曲线。这些数据提供了对氟卡尼在心脏钠通道中作用的分子机制的进一步理解，并证明了一种新的分子工具在研究与心脏病相关的突变钠通道中的氟卡尼作用中的实用性。

著录项

  • 作者

    Atkins, Joshua Henry.;

  • 作者单位

    Columbia University.;

  • 授予单位 Columbia University.;
  • 学科 Chemistry Organic.; Health Sciences Pharmacology.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 231 p.
  • 总页数 231
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 有机化学;药理学;细胞生物学;
  • 关键词

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