Influence of Aromatic-Group Structure on Cardiotropic Activity of Alkoxyphenyltriazaalkanes

Previously, ALM-802 ( N 1 -(2,3,4-trimethoxybenzyl)- N 2 -{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride) and ALM-803 ( N 1 -(3,4,5-trimethoxybenzyl)- N 2 -{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 Ca 2+ -channel blocker verapamil, were synthesized by us. These compounds possessed anti-ischemic and antiarrhythmic activities. Herein, the new compound ALM-843 ( N 1 -(3,4-dimethoxybenzyl)- N 2 -{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 Ca 2+ -channel.