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

Abstract

P-Hydroxy-N-(2-diethylaminoethyl)benzamide (2), the p-hydroxy isostere of procainamide (1), shows antiarrhythmic activity against aconitine-induced atrial arrhythmia and lowers mean arterial blood pressure after i.v. infusion in dogs. In isolated canine Purkinje fibers, phenolic 2 in a bath concentration of 20 .mu.g/ml significantly reduced the rate of phase 0 depolarization, prolonged the repolarization time, and reduced automaticity. These activities of phenolic 2 were similar to those observed for procainamide 1. Bioisosteres, phenolic 2 and procainamide 1, have almost identical respective 13C NMR chemical shifts indicating that electron densities on the respective C 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(.dbd.O)CH3] on the aromatic ring possess more antiarrhythmic activity in mice than the analogue with an electron-withdrawing group (NO2). A shift in electron density toward the amide region in the former analogues, as determined by 13C NMR spectroscopy, probably is a factor influencing antiarrhythmic potency in this series.