Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
PLoS One. 2010 Dec 20;5(12):e15568. doi: 10.1371/journal.pone.0015568.
There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity: ∼25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds.
METHODOLOGY/PRINCIPAL FINDINGS: A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity: We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0.
CONCLUSIONS/SIGNIFICANCE: The correlations of inhibition properties both with chemical properties and therapeutic profiles would not have been evident through the sole determination of IC(50); therefore, recording multiple properties of inhibition may allow improved prediction of therapeutic usefulness.
钠离子通道上只有一个已确定的药物结合位点。然而，钠离子通道的药物结合表现出极高的混杂性：在被研究的药物中，约有 25%被发现能强有力地抑制钠离子通道。这些分子的结构多样性表明，它们可能不共享结合位点，和/或作用方式。我们的目标是通过测量电生理学实验中抑制的多个特性，尝试对钠离子通道抑制剂进行分类。我们还旨在研究抑制的不同特性是否与化合物的特定化学性质相关。
方法/主要发现：使用表达 rNav1.2 的 HEK-293 细胞和 QPatch 自动膜片钳仪器，对 35 种化合物（包括经典的钠离子通道抑制剂（抗惊厥药、抗心律失常药和局部麻醉药），以及抗抑郁药、抗精神病药和神经保护剂）进行了比较电生理学研究。在由抑制的八个特性（静息和失活亲和力、效力、可逆性、起始和终止的时间常数、使用依赖性和状态依赖性）定义的多维空间中，至少可以识别出三种不同类型的抑制；这些可能反映了不同的作用方式。根据相关化学性质（包括亲脂性、芳香性、分子大小、极性和电荷）定义的多维空间中，化合物也以相似的方式聚类。具有相同治疗适应症的药物通常属于同一类型。我们确定了对确定特定抑制特性很重要的化学性质。状态依赖性与亲脂性、分子中性形式的比例和芳香性相关：我们注意到，高度状态依赖性抑制剂至少有两个芳环、logP>4.0 和 pKa<8.0。
结论/意义：通过单独确定 IC50，抑制特性与化学性质和治疗谱的相关性不会明显显现；因此，记录抑制的多个特性可能允许改善对治疗用途的预测。
