Previously, ALM-802 (N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride) and ALM-803 (N1-(3,4,5-trimethoxybenzyl)-N2-{2-[(3,4,5-trimethoxybenzyl) amino]ethyl}-1,2-ethanediamine trihydrochloride), which combined pharmacophores of the free fatty-acid oxidation inhibitors trimetazidine and ranolazine and the slow Ca2+-channel blocker verapamil, were synthesized by us. These compounds possessed anti-ischemic and antiarrhythmic activities. Herein, the new compound ALM-843 (N1-(3,4-dimethoxybenzyl)-N2-{2-[(3,4-dimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride), which exhibited only antiarrhythmic activity, was prepared. The results led to the hypothesis that the antiarrhythmic activity of the linear alkoxyphenyltriazaalkanes was due to the presence of a 3,4-dimethoxyphenyl pharmacophore, which is also present in verapamil. This hypothesis was confirmed using molecular docking to show that the above alkoxyphenyltriazaalkanes bound similarly to the verapamil binding site of the voltage-gated Ca2+-channel.

中文翻译：

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芳基结构对烷氧基苯基三氮杂烷烃心脏活性的影响

此前，ALM-802（N1-（2,3,4-三甲氧基苄基）-N2-{2-[（2,3,4-三甲氧基苄基）氨基]乙基}-1,2-乙二胺三盐酸盐）和ALM-803（ N1-(3,4,5-三甲氧基苄基)-N2-{2-[(3,4,5-三甲氧基苄基)氨基]乙基}-1,2-乙二胺三盐酸盐)，结合游离脂肪酸氧化的药效团我们合成了抑制剂曲美他嗪和雷诺嗪以及慢速钙离子通道阻滞剂维拉帕米。这些化合物具有抗缺血和抗心律失常活性。在此，新化合物ALM-843（N1-（3,4-二甲氧基苄基）-N2-{2-[（3,4-二甲氧基苄基）氨基]乙基}-1,2-乙二胺三盐酸盐）仅表现出抗心律失常活性，准备好了。结果导致假设线性烷氧基苯基三氮杂烷烃的抗心律失常活性是由于存在 3, 4-二甲氧基苯基药效团，也存在于维拉帕米中。使用分子对接证实了这一假设，以表明上述烷氧基苯基三氮杂烷烃与电压门控 Ca2+ 通道的维拉帕米结合位点的结合类似。