AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
批准号:
6494838
负责人:
DIRK SNYDERS
金额:
$18.66万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-08-01 至 2002-07-31
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
中文摘要
在初步的研究中,我们已经确定了一种激动剂的作用,
典型的离子通道阻断剂 这是研究的总目标
在这个项目中,进一步确定这一机制,
效应,在此定义为通道门控的修改,
药物诱导的电流增加,在电压范围内,
心脏动作电位的平台期。 我们迄今为止的研究
已经证明了对Kv1.5介导电流的这种作用,
奎尼丁,由局部麻醉剂布比卡因,并通过
二十二碳六烯酸(鱼类中主要的多不饱和脂肪酸
油)和奎尼丁对HERG介导的电流的影响。 的
拟进行的实验将使用这些药物来研究激动剂的作用
在Kv1.5、Herge和Kv4.3上,这些基因的产物是主要的
人延迟整流和瞬时整流的α亚单位
外向电流 具体目标1将使用生物物理方法
为了检验存在特异性结合位点的假设,
激动剂的作用,并将分析这些结果方面的先进的
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性质;
这项工作可能导致鉴定或合成更纯的
激动剂具体目标3的目标是确定
激动剂作用的结合位点的位点;工作位点
假设与电压传感器(S4)或其
~canaliculus~负责。减少的离子电流越来越多地
被认为是心律失常的潜在因素,因此进一步
对这种激动剂效应的理解应该是重要的
对新药开发的影响。 更一般地说,
众所周知,患者对以下问题的反应差异很大:
抗心律失常药物;拮抗剂和迄今为止的共存-
在单分子中未被识别的激动剂作用具有重要的
对理解这种变化的影响。
英文摘要
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.
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AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
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批准号:6355577
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项目类别:
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资助金额:$21.25万
-
财政年份:2000
-
负责人:DIRK SNYDERS
-
依托单位:
AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
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批准号:6202321
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项目类别:
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资助金额:$21.25万
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财政年份:1999
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负责人:DIRK SNYDERS
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依托单位:
AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
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批准号:6110085
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项目类别:
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资助金额:$21.25万
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财政年份:1998
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负责人:DIRK SNYDERS
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依托单位:
AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS
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批准号:6242136
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项目类别:
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资助金额:$20.61万
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财政年份:1997
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负责人:DIRK SNYDERS
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依托单位:
海外基金