Quantitative structure activity studies of antiarrhythmic properties in a series of lidocaine and procainamide derivatives.

The use- and voltage-dependent depression of the maximum upstroke velocity of the cardiac action potential by a series of lidocaine and procainamide derivatives was studied in guinea pig papillary muscles. The derivatives were chosen to test the effects of the structural and physicochemical differences between lidocaine and procainamide on the kinetics of sodium channel block. Three derivatives were similar to lidocaine with a rapid onset of use-dependent block at fast stimulation rates and short time constants of recovery at normal resting potentials. Seven derivatives were similar to procainamide having slower rates of block development and longer recovery time constants. In order to quantify the differences in sodium channel block the data were analyzed by a model based on the modulated receptor hypothesis. This hypothesis proposes that each of the sodium channel states (rested, open and inactivated) has characteristic association and dissociation rate constants for each sodium channel blocker, drug bound channels do not conduct sodium and have altered inactivation kinetics. This model was solved for the dissociation constants of the drug for the rested and open states, the association and dissociation rate constants for the inactivated channels and the voltage shift of the inactivation kinetics for drug-bound channels. Quantitative structure-activity analysis on the derived parameters revealed that the affinity of the drugs for the open channel state is related to the compounds lipid solubility, the degree of voltage shift was proportional to molecular weight and the dissociation from the inactivated channels was correlated with both the molecular weight and charge.