Antiarrhythmic activity of p-hydroxy-N-(2-diethylaminoethyl) benzamide (the p-hydroxy isostere of procainamide) in dogs and mice.

p-Hydroxy-N-(2-diethylaminoethyl)benzamide (2), the p-hydroxy isostere of procainamide (1), shows antiarrhythmic activity against acontine-induced atrial arrhythmia and lowers mean arterial blood pressure after iv infusion in dogs. In isolated canine Purkinje fibers, phenolic 2 in a bath concentration of 20 mug/ml significantly reduced the rate of phase O depolarization, prolonged the repolarization time, and reduced automaticity. These in vitro and the above in vivo activities of phenolic 2 were similar to those observed for procainamide (1). Bioisosters, phenolic 2 and procainamide (1), have almost identical respective 13C NMR chemical shifts indicating that electron densities on the respective carbons are very similar. This may explain their similar antiarrhythmic and hypotensive effects. Phenolic 2 and procainamide (1) therapeutic ratios in ICR male mice (acute LD50/ED50 against chloroform hypoxia induced ventricular fibrillation) are 2.1 and 1.8, respectively. Procainamide analogues with electron-donating groups [OH, NH2, NHC(=O)CH3] on the aromatic ring possess more antiarrhythmic activity in mice than the analogue with an electron-withdrawing group (NO2). This indicates that a shift in electron density toward the amide region in the former analogues, as determined by 13C NMR spectroscopy, is one of the factors influencing antiarrhythmic potency in this series.