CARDIAC CHANNELS--TARGETS OF DRUGS THAT AFFECT KINETICS

心脏通道——影响动力学的药物靶标

• 批准号: 6651146
• 负责人: DOROTHY A. HANCK
• 金额: $ 29.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651146
• 关键词: Xenopus oocyte; binding sites; calcium channel; calcium channel blockers; electrophysiology; pharmacokinetics; site directed mutagenesis; sodium channel; tissue /cell culture; verapamil; voltage gated channel

DESCRIPTION (Verbatim from Investigator's Abstract): Experiments proposed are aimed at determining structural similarities of drug binding sites between channel types for mibefradil (the only highly specific agent for T-type Ca channels known at the present time) and phenylalkylamines, the drug class that competes with mibefradil, and for which some structural information is available for L-type calcium channels. Three channels will be used, the T-type Ca channel alpha lH, as a high affinity target for mibefradil and a somewhat lower affinity target of verapamil, the voltage-gated Na channel, a very low affinity target for mibefradil but a moderate affinity target for verapamil, and HERG, a high affinity target for both mibefradil and verapamil. In each area, experiments proposed combine site-directed mutagenesis, electrophysiology, and molecular modeling. In addition, experiments are proposed that will establish the channel specific or common effects on kinetics that control the action and efficacy of these agents as therapeutic drugs.

描述（逐字摘自研究者摘要）：拟定的实验是 目的是确定药物结合位点的结构相似性， 米贝拉地尔的通道类型（唯一高度特异性的T型Ca 目前已知的通道）和苯基烷基胺， 与米贝拉地尔竞争，并且其中一些结构信息是 可用于L型钙通道。将使用三个通道，T型 Ca通道α 1H，作为米贝拉地尔的高亲和力靶点， 维拉帕米的低亲和力靶点，电压门控Na通道，一个非常低的 对米贝拉地尔的亲和力靶点，但对维拉帕米的中等亲和力靶点， 和HERG，米贝拉地尔和维拉帕米的高亲和力靶点。在每个 领域，实验提出了联合收割机定点诱变， 电生理学和分子建模。此外，实验还 提出，将建立通道的具体或共同的影响动力学 控制这些药剂作为治疗药物的作用和功效。