CARDIAC CHANNELS--TARGETS OF DRUGS THAT AFFECT KINETICS

描述（逐字记录来自研究者的摘要）：提出的实验是 旨在确定药物结合位点的结构相似性 米贝拉地尔的通道类型（唯一针对 T 型 Ca 的高度特异性药物） 目前已知的通道）和苯烷基胺，该药物类别 与米贝拉地尔竞争，其一些结构信息是 适用于 L 型钙通道。将使用三个通道，T 型 Ca 通道 alpha lH，作为米贝拉地尔的高亲和力靶标，在一定程度上 维拉帕米的较低亲和力靶标，即电压门控 Na 通道，非常低 米贝拉地尔的亲和力目标，但维拉帕米的中等亲和力目标， HERG，米贝拉地尔和维拉帕米的高亲和力靶标。在每个 领域，提出的实验结合定点诱变， 电生理学和分子建模。此外，实验还有 提议将建立通道对动力学的特定或共同影响 控制这些药物作为治疗药物的作用和功效。

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.