Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel

Abstract 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.