AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS

抗心律失常药物的激动作用

• 批准号: 6355577
• 负责人: DIRK SNYDERS
• 金额: $ 21.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355577
• 关键词: antiarrhythmic agent; cell line; chemical structure function; drug receptors; drug screening /evaluation; electrophysiology; heart electrical activity; heart pharmacology; ion channel blocker; local anesthetics; mathematical model; omega 3 fatty acid; pharmacokinetics; potassium channel; protein structure function; quinidine; receptor binding; site directed mutagenesis; stimulant /agonist; voltage gated channel

In preliminary studies, we have identified an ~agonist~ action of prototypical ion channel blockers. It is the overall goal of studies in this Project to further determine mechanisms underlying this effect, defined here as a modification of channel gating that leads to a drug-induced increase in current in the voltage range of the plateau phase of the cardiac action potential. Our studies to date have demonstrated such an effect on Kv1.5-mediated currents by quinidine, by the local anesthetic bupivacaine, and by docosahexaenioc acid (the main polyunsaturated fatty acid in fish oils) and on HERG-mediated currents by quinidine. The experiments proposed will use these agents to study agonist effects on Kv1.5, Herge, and Kv4.3, genes whose products are major alpha-subunits underlying human delayed rectifier and transient outward currents. Specific Aim 1 will use biophysical approaches to test the hypothesis that a specific binding site exits for the agonist effect, and will analyze these results in terms of advanced gating models. Specific Aim 2 will identify physicochemical properties of individual drugs that determine the agonist action; this work may lead to identification or synthesis of ~purer~ agonist. The goal of Specific Aim 3 is to identify the molecular locus of a binding site for the agonist effect; the working hypothesis is that an interaction with the voltage sensor (S4) or its ~canaliculus~ is responsible. Reduced ion current is increasingly recognized as a potential contributor to arrhythmias, so further understanding of this agonist effect should have important implications for new drug development. More generally, it is well-recognized that patients vary widely in their responses to antiarrhythmic drugs; the coexistence of antagonist and heretofore- unrecognized agonist effect in single molecules has important implications for understanding this variability.

在初步研究中，我们已经确定了一种~激动剂~作用 原型离子通道阻滞剂。 这是学习的总体目标 在此项目中进一步确定其背后的机制 效应，此处定义为通道门控的修改，导致 药物引起的电压范围内电流增加 心脏动作电位的平台期。 迄今为止我们的研究 已经证明了对 Kv1.5 介导的电流的这种影响 奎尼丁，局部麻醉剂布比卡因，以及 二十二碳六烯酸（鱼中主要的多不饱和脂肪酸 油）和奎尼丁介导的 HERG 电流。 这 拟议的实验将使用这些药物来研究激动剂效应 Kv1.5、Herge 和 Kv4.3，其产物主要的基因 人类延迟整流器和瞬态的α亚基 向外的电流。 具体目标 1 将使用生物物理方法 检验存在特定结合位点的假设 激动剂效应，并将在高级方面分析这些结果 门控模型。 具体目标 2 将确定物理化学 决定激动剂作用的单个药物的特性； 这项工作可能会导致〜更纯〜的鉴定或合成 激动剂。具体目标 3 的目标是识别分子 激动剂效应的结合位点的位点；工作的 假设是与电压传感器（S4）或其 ~canaliculus~ 负责。减少的离子电流越来越多 被认为是心律失常的潜在因素，因此进一步 了解这种激动剂效应应该具有重要意义 对新药开发的影响。 更一般地说，它是 众所周知，患者对药物的反应差异很大 抗心律失常药物；对手与迄今为止的共存 单分子中未被识别的激动剂效应具有重要意义 对理解这种变异性的影响。