CARDIAC CHANNELS--TARGETS OF DRUGS THAT AFFECT KINETICS

描述(逐字摘自《调查人员摘要》)：建议的实验包括 目的是确定药物结合部位的结构相似性 米贝拉地尔(治疗T型病例的唯一高度特异性药物)的通道类型 目前已知的通道)和苯烷基胺，这类药物 与mibefradil竞争，其一些结构信息是 适用于L型钙离子通道。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 低亲和力靶点的维拉帕米，电压门控钠通道，一个非常低的 米贝拉地尔的亲和力靶标但维拉帕米的中等亲和力靶标， 和HERG，米贝法地尔和维拉帕米的高亲和力靶点。在每一个中 区域，提出了结合定点突变的实验， 电生理学和分子建模。此外，实验还包括 提出将建立通道特定或共同的对动力学的影响 控制这些药物作为治疗药物的作用和效果。

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.