Drayer D E, Slaven B H, Reidenberg M M, Bagwell E E, Cordova M
J Med Chem. 1977 Feb;20(2):270-4. doi: 10.1021/jm00212a017.
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.
对羟基 - N -（2 - 二乙氨基乙基）苯甲酰胺（2）是普鲁卡因酰胺（1）的对羟基电子等排体，对乌头碱诱发的犬房性心律失常具有抗心律失常活性，静脉输注后可降低犬的平均动脉血压。在离体犬浦肯野纤维中，浴槽浓度为20μg/ml的酚类化合物2显著降低0期去极化速率，延长复极化时间，并降低自律性。酚类化合物2的这些体外活性和上述体内活性与普鲁卡因酰胺（1）观察到的活性相似。生物电子等排体酚类化合物2和普鲁卡因酰胺（1）具有几乎相同的各自的13C NMR化学位移，表明各自碳原子上的电子密度非常相似。这可能解释了它们相似的抗心律失常和降压作用。酚类化合物2和普鲁卡因酰胺（1）在ICR雄性小鼠中的治疗比率（针对氯仿缺氧诱发的心室颤动的急性LD50/ED50）分别为2.1和1.8。在芳环上带有供电子基团[OH、NH2、NHC(=O)CH3]的普鲁卡因酰胺类似物在小鼠中比带有吸电子基团（NO2）的类似物具有更强的抗心律失常活性。这表明，如通过13C NMR光谱法所确定的，在前述类似物中电子密度向酰胺区域的转移是影响该系列抗心律失常效力的因素之一。
