Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O.B. 67, H-1450 Budapest, Hungary.
Neuropharmacology. 2011 Jan;60(1):191-200. doi: 10.1016/j.neuropharm.2010.08.005. Epub 2010 Aug 14.
Sodium channels are inhibited by a chemically diverse group of compounds. In the last decade entirely new structural classes with superior properties have been discovered, and novel therapeutic uses of sodium channel inhibitors (SCIs) have been suggested. Many promising novel drug candidates have been described and characterized. Published structure-activity relationship studies, pharmacophore models, and mutagenesis studies seem to lag behind, dealing with only a limited group of inhibitor compounds. The abundance of novel compounds requires an organized comparison of drug potencies. The affinity of sodium channel inhibitors can vary typically ten- to thousand-fold depending on the voltage protocol; therefore comparison of electrophysiology data is difficult. In this study we describe a method for standardization of these data with the help of a simple model of state-dependence. We derived hyperpolarized (resting) and depolarized (generally termed "inactivated") state affinities for the studied drugs, which made the measurements comparable. We show a rank order of SCIs based on resting and inactivated affinity values. In an attempt to define basic chemical requirements for sodium channel inhibitor activity we investigated the dependence of both resting and inactivated state affinities on individual chemical descriptors. Lipophilicity (most often expressed by the logP value) is the single most important determinant of SCI potency. We investigated the independent impact of several other calculated chemical properties by standardizing drug potencies for logP values. By combining these two approaches: standardization of affinity values, and standardization of potencies, we concluded that while resting affinity is mostly determined by lipophilicity, inactivated state affinity is determined by a more complex interaction of chemical properties, including hydrogen bond acceptors, aromatic rings, and molecular weight.
钠离子通道被化学结构多样的化合物所抑制。在过去十年中，人们发现了全新结构类别、具有卓越性能的化合物，并提出了钠离子通道抑制剂（SCIs）的新治疗用途。许多有前途的新型药物候选物已经被描述和表征。已发表的构效关系研究、药效团模型和突变研究似乎滞后，只涉及有限数量的抑制剂化合物。新型化合物的丰富性需要对药物效力进行有组织的比较。钠离子通道抑制剂的亲和力通常因电压方案而异，相差 10 到 1000 倍；因此，电生理学数据的比较很困难。在这项研究中，我们描述了一种使用状态依赖性简单模型对这些数据进行标准化的方法。我们为研究药物得出了超极化（静息）和去极化（通常称为“失活”）状态亲和力，从而使测量具有可比性。我们根据静息和失活亲和力值对 SCIs 进行了排序。为了尝试定义钠离子通道抑制剂活性的基本化学要求，我们研究了静息和失活亲和力值对单个化学描述符的依赖性。亲脂性（通常用 logP 值表示）是决定 SCI 效力的唯一最重要因素。我们通过标准化药物效力来研究 logP 值对亲脂性和失活亲和力的独立影响。通过结合这两种方法：亲和力值的标准化和效力的标准化，我们得出结论，尽管静息亲和力主要由亲脂性决定，但失活状态亲和力由更复杂的化学性质相互作用决定，包括氢键受体、芳环和分子量。
