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The cardioprotective activity of ALM-802 compound was demonstrated in model experiments simulating postinfarction chronic heart failure in rats forming in 90 days after anterior transmural myocardial infarction. ALM-802 decreased the left ventricle and improved its inotropic function (p=0.038). This effect was observed in case of systematic administration of ALM-802 over 28 days (starting from day 91 after infarction modeling). This is apparently the minimum time for the cardioprotective effect of ALM-802 to prevent or treat the resulting heart failure, because short-term systematic therapy (15 days) produced no positive effect.

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The anxiolytic and analgesic properties of compound ALM-802, a cardiotropic linear methoxyphenyltriazaalkane derivative, combining pharmacophore elements of p-FOX inhibitors trimetazidine and ranolazine were studied in vivo. In the elevated plus-maze test, ALM-802 after acute intraperitoneal administration in doses of 1-8 mg/kg dose-dependently prevented the development of anxiety in BALB/c mice. Chronic intraperitoneal administration of ALM-802 in a dose of 2 mg/kg to alcohol-preferring rats attenuated anxiogenesis induced by ethanol withdrawal. ALM-802 demonstrated antinociceptive activity in C57BL/6 mice during thermal stimulation of nociceptors in the hot plate test and during modeling of visceral pain in the acetic acid writhing test. Thus, ALM-802 exhibits anxiolytic and analgesic properties in the dose range corresponding to its anti-ischemic and antiarrhythmic effects.

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Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 µg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.

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The antiarrhythmic activity and acute toxicity of a series of 2-(2'-hydroxy-2')-substituted ethyloctahydropyrrolo[1,2-a]pyrazines were studied. Two most promising compound (PV-238) is characterized by high antiarrhythmic activity, broad spectrum of action, and low toxicity.

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The antiarrhythmic activity and acute toxicity of a series of 2-(2'-hydroxy-2'-substituted) ethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazines were studied. Two most promising compounds (PV-168 PV-174) are characterized by a high antiarrhythmic activity, a broad spectrum of action, and low toxicity.

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The binding of N-substituted aminocarboxylic acid dicyclohexylamide (NACA-DCHA) derivatives to M-1 muscarinic cholinoreceptors (MRs) in rat brain cortex and and beta-1 adrenoreceptors (ARs) in rat heart was studied. The maximum MR affinity was observed for AL-275 (IC50, 2.8 microM) and AL-315 (IC 50, 3.2 microM) preparations. The other compounds (except AL-310 with IC50 > 100 microM) interacted with MR at a lower affinity. The binding to beta-1 AR in rat heart was observed for a single preparation AL-298 (IC50, 38 microM). The antimuscarinic activity of some NACA-DCHA derivatives, especially AL-275 and AL-315) may play a significant role in realization of the antiarrhythmic activity.

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Experiments on arrhythmia models showed a high antiarrhythmic activity of new derivatives of dicyclohexylamides of N-replaced alpha-aminocarbonic acids. The new compounds surpassed in intensity and duration of the antiarrhythmic effect the standard agents with classes I and III antiarrhythmic activity. In doing so they raise myocardial electrical stability and prevent sudden development of ventricular fibrillation. According to the mechanism of the antiarrhythmic activity, the new compounds may be related to antiarrhythmic agents possessing the properties of classes I and III.

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The Institute of Pharmacology, Academy of Medical Sciences, jointly with AWD (Germany) has synthesized and tested a novel class III antiarrhythmic coded AWD-160-275, a derivative of dicyclohexylamides of aminocarboxylic acids. The compound was shown to prolong cardiac repolarization, to increase atrial and ventricular refractory periods, to decrease sinus nodal automatism, and to unchange intraventricular conduction. The compound proved to be superior to the reference drugs in the rate and duration of antiarrhythmic and antifibrillatory action. In therapeutical doses it has no antiarrhythmic effect. The specific feature of the agent is that there is no relation of longer effective refractory periods to the frequency of stimulation. This property may be useful in treating tachyarrhythmias.

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Specific binding of dialkylaminoacyl (DAC) derivatives of phenothiazine, dibenzazepine, dibenzdiazepine with opiate receptors (OR) of mu- and delta-subtypes was studied. Some of the compounds studied exhibit moderate affinity to mu-OR in microM range. Binding with delta-OR is less pronounced. Dibenzdiazepine derivative AL-234 is the most potent compound with respect to OR of both mu- and delta- subtypes (IC50 values were 11 and 60 microM, respectively). The ability of DAC- derivatives to bind specifically OR can play a decisive role in realization of their pharmacologic properties, namely antinociceptive and probably antiarrhythmic activity.

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The antiarrhythmic properties of the dibenzazepine derivative bonnecor and derivatives of mesidides of alpha-azacycloalkanocarboxylic acids were studied in various experimental arrhythmia models. The comparative study revealed different antiarrhythmic effects in different arrhythmia models. Bonnecor was found to have a higher antiarrhythmic activity in most arrhythmic models. Tertiary salts were demonstrated to be more potent than quaternary ones.

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A high antiarrhythmic activity of arylamides of alpha-hexamethyleniminocarbonic acids was found on different experimental models of arrhythmias. It was shown that the lengthening of the carbonic chain in carbonic acids (R) as well as the change from ortho-toluidides to xylidides or mesidides in the aromatic fragment of the molecule increased the antiarrhythmic activity of the studied compounds, their toxicity also increased. The choice of compounds with optimal properties is determined by the combination of all investigated factors: intensity and duration and also the specific features of the spectrum of the antiarrhythmic effect, toxicity and therapeutic range.

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The synthesis of the title compounds is described. The compounds are characterized by having no cataleptogenic effect and no antagonistic effect against amphetamine stereotypies in experimental animals. The pharmacological results of the rota-rod, spontaneous motility, aggression-test, hexobarbital-potentiation and antagonism to physostigmine are reported.

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