Cardiac Channels: Targets of Drugs that Affect Kinetics

心经：影响动力学的药物靶点

• 批准号: 7822235
• 负责人: DOROTHY A. HANCK
• 金额: $ 1.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822235
• 关键词: Action Potentials; Adverse effects; Affect; Affinity; Amlodipine; Antihypertensive Agents; Binding; Blood Pressure; CYP3A4 gene; Calcium Channel Binding; Calcium Channel Blockers; Cardiac; Cause of Death; Cells; Charge; Clinical; Clinical Trials; Coronary heart disease; Country; Coxibs; Dependence; Dihydropyridines; Disease; Drug Delivery Systems; Drug Design; Drug Interactions; Electrophysiology (science); Enzymes; Epitopes; Fluorescence; Generations; Goals; Grant; Heart; Heart Diseases; Hypertension; Hypotension; Ion Channel; Kinetics; L-Type Calcium Channels; Laboratories; Link; Location; Marketing; Mechanics; Membrane Potentials; Mibefradil; Modeling; Molecular; Molecular Conformation; Molecular Models; Movement; Mutagenesis; Paroxysmal Atrial Tachycardia; Pharmaceutical Preparations; Principal Investigator; Reporting; Risk; Rofecoxib; Site; Smooth Muscle; Specificity; Stroke; T-Type Calcium Channels; Techniques; Testing; Therapeutic Agents; Vascular System; Verapamil; base; comparative; computerized; cross reactivity; dihydropyridine; effective therapy; efonidipine; experience; molecular modeling; phenylalkylamine; programs; prototype; voltage

DESCRIPTION (provided by applicant): Cardiac disease continues to be the leading cause of death in this country. Drugs that affect blood pressure are important therapeutic agents, and calcium channel blockers have been validated in a number of large clinical trials as effective in not only lowering blood pressure but also in reducing the risks of coronary heart disease and stroke. Although they are generally thought to preferentially block L-type calcium channels in the vascular system, some of them have also been reported to block T-type calcium channels as well. We propose to investigate the binding determinants and molecular basis of inhibition of three calcium channel blockers: mibefradil, as a prototype drug for which the T-type calcium channel is the primary target, verapamil, a first generation calcium channel blocker (phenylalkylamine), which continues to be effective for treatment of hypertension and also is a first line therapy for paroxysmal atrial tachycardia, and amlodipine, a highly prescribed fourth generation dihydropyridine (DHP). Our experimental focus will be on the T-type calcium channel as an important primary or secondary target of these drugs, although we also propose to collaborate with an L-channel laboratory for comparative analysis between drugs and T- and L-channels and to study voltage dependent Na channels as a secondary target of mibefradil. Our long term goal is to understand the control of the molecular substrate of drugs that target cardiac ion channels, i.e. the structural bases of their state dependent affinities. We have chosen these three agents because they are classes of therapeutic agents that are relevant to or attractive for clinical use, interact with T-channels in distinct ways, and provide us with the opportunity to discover important structural determinants of kinetic function. Our strategy combines mutagenesis, whole cell, single channel, and gating current electrophysiology, and molecular modeling.

描述（由申请人提供）：心脏病仍然是这个国家的主要死亡原因。影响血压的药物是重要的治疗药物，钙通道阻滞剂已在许多大型临床试验中被证实不仅能有效降低血压，而且能降低冠心病和中风的风险。虽然它们通常被认为优先阻断血管系统中的L型钙通道，但也有报道称它们中的一些也阻断T型钙通道。我们建议研究三种钙通道阻滞剂抑制的结合决定簇和分子基础：米贝拉地尔是以T型钙通道为主要靶点的原型药物，维拉帕米是第一代钙通道阻滞剂（苯基烷基胺），其对于高血压的治疗仍然有效并且也是阵发性房性心动过速的一线疗法，以及第四代二氢吡啶（DHP）。我们的实验重点将是T型钙通道作为这些药物的一个重要的主要或次要目标，虽然我们也建议与L-通道实验室合作，药物和T-和L-通道之间的比较分析，并研究电压依赖性钠通道作为米贝拉地尔的次要目标。我们的长期目标是了解靶向心脏离子通道的药物的分子底物的控制，即它们的状态依赖性亲和力的结构基础。我们选择了这三种药物，因为它们是与临床使用相关或有吸引力的治疗药物，以不同的方式与T通道相互作用，并为我们提供了发现动力学功能的重要结构决定因素的机会。我们的策略结合了诱变，全细胞，单通道，门控电流电生理学和分子建模。