Study of the N1-(2,3,4-Trimethoxybenzyl)-N2-{2-[(2,3,4-Trimethoxybenzyl)Amine]Ethyl}-1,2-Ethandiamine Compound Effect on the Physical Performance of Animals.

We studied the effect of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine (compound ALM-802) on the physical performance of mice after acute fatigue. The animals' performance was assessed on a treadmill. The criterion for assessing exercise tolerance was the length of the distance passed when running on a treadmill until complete fatigue. To assess the actoprotective activity of compound ALM-802, we used a method of stepwise increase in load with an initial running speed of 42 cm/sec and its subsequent increase by 5 cm/sec every 5 min. The maximum speed of movement of the treadmill belt is 77 cm/sec. Animals that received compound ALM-802 (2 mg/kg intraperitoneally), 1 day after acute fatigue, ran a distance to complete fatigue that exceeded that of control mice by 68% (387.9±60.5 and 230.6±29.6 m, respectively, p=0.023). The reference drug trimetazidine (30 mg/kg, intraperitoneally) did not have a significant effect on the distance traveled. Compound ALM-802 helps restore physical performance, i.e. exhibits significant actoprotective activity.

To the Mechanism of the Antiarrhythmic Action of Compound ALM-802: the Role of Ryanodine Receptors.

The effect of the compound N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) on the amplitude of the Ca2+ response in the cell was studied in in vitro experiments. The concentration of intracellular calcium was assessed using a Fura-2 two-wave probe. The experiments were performed on a culture of isolated rat hippocampal neurons. The effect of compound ALM-802 on the activity of ryanodine receptors (RyR2) was studied on an isolated strip of rat myocardium. The compound ALM-802 (69.8 µM) in hippocampal neurons causes a significant decrease in the amplitude of the Ca2+ response induced by addition of KCl to the medium. Experiments performed on an isolated myocardial strip showed that compound ALM-802 (10-5 M) almost completely blocked the positive inotropic reaction of the strip to the RyR2 agonist caffeine (5×10-5 M). The data obtained indicate that the decrease in the concentration of Ca2+ ions in the cell caused by ALM-802 is due to its ability to block RyR2 located on the membrane of the sarcoplasmic reticulum, which can be associated with the antiarrhythmic activity of the compound.

Mechanisms Underlying the Antiarrhythmic Action of Compound ALM-802.

The mechanisms underlying the antiarrhythmic action of compound trihydrochloride N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) were studied in vitro. The experiments were performed on a culture of rat hippocampal neurons. The electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It is shown that the compound ALM-802 effectively blocks potential-dependent Na+ and K+ channels and does not affect the activity of potential-dependent Ca2+ channels. The inhibition of currents through these channels is dose-dependent; the IC50 of Na+ and K+ channels were 94±4 and 67±3 µM, respectively. These findings indicate that compound ALM-802 combines the properties of class I and class III antiarrhythmic agents according to the Vaughan-Williams classification.