The sodium channel as a target for local anesthetic drugs.
The sodium channel as a target for local anesthetic drugs.
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DOI：
10.3389/fphar.2011.00068
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发表时间：
2011
影响因子：
5.6
通讯作者：
Hanck DA
中科院分区：
文献类型：
--
作者：
Fozzard HA;Sheets MF;Hanck DA
Na通道是神经系统和肌肉兴奋电流的来源。它们是一类称为局部麻醉剂（LA）的药物的靶点，这些药物已用于局部和区域麻醉以及兴奋性问题，如癫痫和心律失常。这些药物是新型止痛药的原型。药物结合位点已定位于通道的内孔，其中药物主要与结构域IV S6中的苯丙氨酸相互作用。药物亲和力是电压依赖性和使用依赖性的。电压依赖性是通道激活和开放期间内孔构象变化的结果，允许药物与苯丙氨酸的高能相互作用。LA药物还降低Na通道的门控电流，其代表电压传感器中带电残基的移动。具体地，药物与苯丙氨酸的结合将结构域III S4锁定在其向外（活化）的位置，并减缓结构域IV S4的恢复。虽然强烈影响门控，LA药物几乎肯定也通过空间阻塞的孔。结合和阻断相互作用的分子定义可能有助于新药开发。
Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA), which have been used for local and regional anesthesia and for excitatory problems such as epilepsy and cardiac arrhythmia. These drugs are prototypes for new analgesic drugs. The drug-binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated) position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development.
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影响因子：
16.2
作者：
CHAHINE, M;GEORGE, AL;HORN, R
通讯作者：
HORN, R
影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
DOI：
10.1073/pnas.83.2.508
发表时间：
1986-01-01
影响因子：
11.1
作者：
GUY, HR;SEETHARAMULU, P
通讯作者：
SEETHARAMULU, P
DOI：
10.1073/pnas.92.25.11839
发表时间：
1995-12-05
影响因子：
11.1
作者：
QU, YS;ROGERS, J;CATTERALL, WA
通讯作者：
CATTERALL, WA
DOI：
10.1073/pnas.89.22.10905
发表时间：
1992-11-15
影响因子：
11.1
作者：
PATTON, DE;WEST, JW;GOLDIN, AL
通讯作者：
GOLDIN, AL