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RS Sheldon, RJ Hill, M Taouis and LM Wilson
Cardiovascular Research Group, University of Calgary, Alberta, Canada.
The structural and physicochemical determinants of binding of lidocaine and several of its aminoalkyl homologs to specific sites associated with the sodium channel were assessed using a radioligand assay and freshly isolated rat cardiac myocytes. The two series of closely related lidocaine homologs that were studied were composed, first, of homologs differing in the length of the link between the arylamide and amine domains of the molecule and, second, of homologs differing in the number of carbons attached to the terminal amine. Drug affinity was measured with a radioligand binding assay, using [3H]batrachotoxinin A 20 alpha-benzoate and freshly isolated cardiac myocytes. The affinities of the homologs were then compared with the pKa values, partition coefficients, distribution coefficients, and molecular structure of the homologs, to determine the relationship between the affinity for the receptor and the physicochemical and structural properties of the drug. Optimal binding was obtained with a link between the arylamide and amine domains that was two carbons in length. The affinity of the drug for the receptor was optimal with four or more amino-terminal carbons, and the precise arrangement of the carbons was not important. Each of the amino-terminal carbons independently contributed 0.3 kcal of free energy of binding, suggesting that the carbons dissolve in a hydrophobic pocket. The evolving picture of a drug structure that is optimal for receptor binding is one of a compound with a two-carbon arylamide-amine link and four or more amino-terminal carbons.
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