Abstract

Our purpose was to assess the structural and physicochemical determinants of the binding of tocainide and several of its homologs to the class I antiarrhythmic drug receptor associated with rat cardiac sodium channels. The homologs were chosen to assess the contributions of substituents of the aryl ring and the arylamine link on drug binding. Drug affinity was measured with a radioligand binding assay using [3H]Batrachotoxin A 20 alpha-Benzoate and freshly isolated cardiac myocytes. The affinities of the homologs were compared to determine the relationship between the affinity for the receptor and the physicochemical and structural properties of the parent drug. The contributions to the free energy of binding were determined with the Gibb's equation delta G = -RT In (1/Ki). Hydrophobic interactions are important at most sites. Meta substituents on the aryl ring and substituents on the link each interact hydrophobically with the receptor and contribute about 0.3 kcal/mol of carbon. The hydrophobic pocket near the link binding site accommodates at least six carbons. A para methoxy substituent reduces the free energy of tocainide binding by 43%. This profound reduction in the free energy of binding might be due to anomolously high aqueous solubility of alkyl aryl ethers. Longer alkoxy chains contribute 1.09 kcal/mol of carbon to the binding energy. Ortho substituents contribute little to binding specificity. These findings support a notion of a complex drug receptor with hydrophilic and hydrophobic domains that recognize specific moieties on class I antiarrhythmic drugs.