Selective, Direct Activation of High-Conductance, Calcium-Activated Potassium Channels Causes Smooth Muscle Relaxation
Selective, Direct Activation of High-Conductance, Calcium-Activated Potassium Channels Causes Smooth Muscle Relaxation
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选择性、直接激活高电导钙激活钾通道导致平滑肌松弛
DOI：
10.1124/mol.111.075853
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发表时间：
2012
影响因子：
3.6
通讯作者：
M. L. García
中科院分区：
文献类型：
--
作者：
C. Ponte;O. McManus;W. Schmalhofer;D. Shen;G. Dai;A. Stevenson;S. Sur;Tarak Shah;L. Kiss;Min;J. Doherty;R. Nargund;G. Kaczorowski;G. Suarez;M. L. García
高电导钙激活钾（Maxi-K）通道存在于平滑肌中，调节张力。Maxi-K通道的激活导致平滑肌超极化和动作电位持续时间缩短，这将限制钙通过电压依赖性钙通道进入，导致松弛。尽管Maxi-K通道似乎间接介导许多药物的松弛作用，但没有可用于概念验证研究的具有适当效力和药理学性质的直接结合通道的激活剂。迄今为止，大多数确定的代理显示显着的多药作用，严重损害了实验数据的解释。在本研究中，建立了一种用于鉴定Maxi-K通道激动剂的高通量、功能性、基于细胞的测定，并用于筛选大量样品集合（> 160万种化合物）。在效力和选择性的基础上，进一步表征了一个四氢喹啉家族。药物化学的努力提供了化合物X的鉴定，从中分离出其两种对映异构体Y和Z。在体外试验中，Z作为通道激活剂比Y更有效。在组织中观察到相同的特征，其中证明了任一药物通过钾通道依赖性机制舒张预收缩平滑肌的能力。这些数据综合起来表明，Maxi-K通道的直接激活代表了一种有待探索的潜在治疗与平滑肌过度兴奋相关的许多疾病的机制。
High-conductance calcium-activated potassium (Maxi-K) channels are present in smooth muscle where they regulate tone. Activation of Maxi-K channels causes smooth muscle hyperpolarization and shortening of action-potential duration, which would limit calcium entry through voltage-dependent calcium channels leading to relaxation. Although Maxi-K channels appear to indirectly mediate the relaxant effects of a number of agents, activators that bind directly to the channel with appropriate potency and pharmacological properties useful for proof-of-concept studies are not available. Most agents identified to date display significant polypharmacy that severely compromises interpretation of experimental data. In the present study, a high-throughput, functional, cell-based assay for identifying Maxi-K channel agonists was established and used to screen a large sample collection (>1.6 million compounds). On the basis of potency and selectivity, a family of tetrahydroquinolines was further characterized. Medicinal chemistry efforts afforded identification of compound X, from which its two enantiomers, Y and Z, were resolved. In in vitro assays, Z is more potent than Y as a channel activator. The same profile is observed in tissues where the ability of either agent to relax precontracted smooth muscles, via a potassium channel-dependent mechanism, is demonstrated. These data, taken together, suggest that direct activation of Maxi-K channels represents a mechanism to be explored for the potential treatment of a number of diseases associated with smooth muscle hyperexcitability.
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DOI：
10.1152/ajprenal.00060.2005
发表时间：
2005-09-01
影响因子：
4.2
作者：
Thorneloe, KS;Meredith, AL;Nelson, MT
通讯作者：
Nelson, MT
DOI：
--
发表时间：
2003
期刊：
American journal of physiology. Renal physiology
影响因子：
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作者：
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通讯作者：
J. Pluznick;P. Wei;P. Carmines;S. Sansom
DOI：
10.1016/j.bbrc.2009.10.091
发表时间：
2009-12-18
影响因子：
3.1
作者：
Bukiya, Anna N.;Vaithianathan, Thirumalini;Dopico, Alejandro M.
通讯作者：
Dopico, Alejandro M.
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DOI：
10.1152/ajpregu.00173.2008
发表时间：
2008
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
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作者：
Werner,MatthiasE;Meredith,AndreaL;Aldrich,RichardW;Nelson,MarkT
通讯作者：
Nelson,MarkT