Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects.
Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects.
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芳基苯并氮卓类药物是延迟整流 K 通道的有效调节剂：其神经保护作用的潜在机制
DOI：
10.1371/journal.pone.0005811
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发表时间：
2009-06-05
期刊：
影响因子：
3.7
通讯作者：
Zhen X
中科院分区：
文献类型：
--
作者：
Chen XQ;Zhang J;Neumeyer JL;Jin GZ;Hu GY;Zhang A;Zhen X
（+/-）SKF 83959与许多其他芳基苯并氮杂卓类药物一样，在体外和体内均具有强大的神经保护作用。发现该化合物的神经保护作用部分依赖于其D（1）样多巴胺受体激动活性。（+/-）SKF 83959介导的神经保护作用的确切机制仍然难以捉摸。我们在此报告（+/-）SKF 83959是一种有效的延迟整流钾通道阻断剂。（+/-）SKF 83959剂量依赖性地抑制大鼠海马神经元延迟整流钾电流（I（K））。抑制I（K）的IC（50）值为41.9+/-2.3 microM（Hill系数= 1.81+/-0.13，n = 6），而抑制I（A）的IC（50）值为307.9+/-38.5 microM（Hill系数= 1.37+/-0.08，n = 6）。因此，（+/-）SKF 83959抑制I（K）的效力是I（A）的7.3倍。此外，（+/-）SKF 83959对I（K）的抑制是电压依赖性的，与多巴胺受体无关。抑制和恢复的快速开始表明抑制是由（+/-）SKF 83959与K（+）通道的直接相互作用引起的。细胞内应用（+/-）SKF 83959对I（K）无影响，提示该化合物可能作用于K（+）通道的外口。我们还测试了（+/-）SKF 83959、R-（+）SKF 83959（MCL-201）和S-（-）SKF 83959（MCL-202）以及SKF 38393的对映体;所有这些化合物均抑制I（K）。然而，（+/-）SKF 83959，无论是0.1或1 mM，表现出最强的抑制电流在所有测试的药物。本研究结果不仅揭示了一种新的有效的I（K）阻断剂，而且还为芳基苯并氮杂卓类药物如（+/-）SKF 83959的神经保护作用提供了一种新的机制。
(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.
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影响因子：
5
作者：
ARNT, J;HYTTEL, J;SANCHEZ, C
通讯作者：
SANCHEZ, C
影响因子：
3.4
作者：
GNANALINGHAM, KK;HUNTER, AJ;MARSDEN, CD
通讯作者：
MARSDEN, CD
影响因子：
4.7
作者：
Panchalingam, S;Undie, AS
通讯作者：
Undie, AS
影响因子：
5.3
作者：
Franciosi, Sonia;Ryu, Jae K.;McLarnon, James G.
通讯作者：
McLarnon, James G.
影响因子：
3.6
作者：
Ahn, Hye Sook;Kim, Sung Eun;Hahn, Sang June
通讯作者：
Hahn, Sang June