Cardiovascular diseases (CVD) are widespread and the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed since the beginning of the 20th century. To date, a large number of cardioprotective agents of various classes have been created. Nevertheless, the need for the development and development of new effective and safe drugs for the treatment of cardiovascular diseases remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward the concept of creating a new generation of cardioprotective drugs with a multi-targeting mechanism of action within the indicated pharmacophore model. This work begins a series of literature reviews devoted to the generalization of currently known compounds with cardioprotective properties in a series of compounds corresponding to the pharmacophore model of linked biaromatic compounds. The first part presented here describes calcium channel blockers with cardioprotective effects.

Thе article represents a review of our own researches, which describes the design, synthesis and pharmacological properties of linear substituted glyproline GZK-111, a potential drug for the complex treatment of psychiatric pathologies, including anxiety, depressive disorders, and cognitive impairment. The relationship between structure and activity in a series of this glyproline analogs is described. The experimental evidence of the GZK-111 ability to metabolized with the formation of cycloprolylglycine, which is identical to the endogenous cyclic dipeptide, is presented. The data on toxicological and pharmacokinetic studies of GZK-111 are presented.

Earlier, in experiments in vitro and in vivo, it was shown that the TrkA receptor agonist compound GK-2, which was a low molecular weight NGF mimetic, had pronounced angiogenic and antiischemic activity. However, it remained unclear whether this activity was associated with the activation of VEGF-A, since, on the one hand, there are reports that NGF-mediated angiogenesis can be initiated by activating NGF of the vascular endothelial growth factor VEGF-A, and on the other hand, it is shown that a selective antagonist of Flk1 receptors specific for VEGF-A, compound SU-5416 does not affect the angiogenic effect of NGF. Purpose of the investigation. Study of the selective VEGF blockade effect on the antiischemic activity of the TrkA receptor agonist GK-2. Methods. Evaluation of the compound GK-2 antiischemic activity was assessed in model experiments simulating hind limb ischemia in rats. Results. It has been shown that against the background of blockade of VEGF-A binding with specific for it (VEGFR1 / Flt-1 / and VEGFR2 / KDR /) receptors, bevacizumab (2.5 mg / kg, i.p., every 3 days for 14 days) compound GK-2 (1 mg / kg, i.p., daily, for 14 days) realizes its antiischemic activity. Conclusion. The results of these experiments indicate that the selective blockade of VEGF does not significantly affect the anti-ischemic activity of the dipeptide NGF mimetic compound GK-2, which has the properties of a TrkA receptor agonist.

The purpose of the study. Investigation of the effect of the fabomotizol dihydrochloride systematic therapy on the morphological picture of the heart left ventricle (LV) in rats in the subacute period of myocardial infarction. Materials and methods. Myocardial infarction (MI) modeling was carried out using the A.Selye method. Fabomotizol dihydrochloride was administered to rats intraperitoneally 1 time per day from the 15th to the 28th day after MI at a dose of 15 mg/kg. At the end of the experiment, euthanasia and a pathoanatomic autopsy were performed. Samples of hearts after fixation in formalin and standard wiring were poured into paraffin blocks. Histological sections of the hearts were microscoped in transmitted light. Results. Dilation of the LV cavity and thinning of its walls in animals treated with fabomotizol dihydrochloride are less pronounced than in control rats with MI. In the periinfarction zone of the myocardium in rats treated with fabomotizol dihydrochloride, wave-like deformation and fragmentation of cardiomyocytes is less intense, and the transverse striation of myofibrils, on the contrary, is more pronounced than in the control. In animals treated with fabomotizol dihydrochloride, the periinfarction zone is well vascularized. Conclusion. According to the results of morphological studies performed on a model of subacute MI in rats, it was demonstrated that systematic therapy with fabomotizole dihydrochloride contributes not only to a significant reduction in the necrosis zone, but also to a certain extent prevents the development of early postinfarction remodeling. In rats treated with fabomotizol dihydrochloride, in contrast to control animals, reparative processes prevail in the cardiac muscle. These observations indicate the presence of cardioprotective activity in the drug.

The purpose of the study. There are investigation of the possibility of using the laser Doppler flowmetry method to assess blood microcirculation and analyze the mechanisms of its regulation in conditionally intact and ischemic myocardium in small laboratory animals (rats) to identify the "coronary theft" syndrome. Materials and methods. The experiments were carried out on white mongrel anesthetized (urethane 1300 mg/kg /b) male rats weighing 200-250 g. 28 days after the reproduction of an experimental myocardial infarction in an open chest and artificial lung ventilation, the microcirculation level was assessed in conditionally intact and ischemic areas of the myocardium by laser Doppler flowmetry. Using spectral wavelet analysis, the amplitudes of microcirculation oscillations normalized to the total perfusion associated with various regulation mechanisms were determined. Results. It was found that the microcirculation level is significantly lower in the ischemic zone of the myocardium compared with the conditionally intact one (17.3±2.8 and 30.3±1.3 per. units, respectively, p = 0.006, n = 8). Spectral wavelet analysis showed that in the ischemic injury zone, in comparison with the conditionally intact myocardium, the amplitudes of microcirculation oscillations normalized to the general level of microcirculation increase for all regulatory mechanisms. Conclusion. The laser Doppler flowmetry method can be used to assess the intensity of microcirculation in conditionally intact and ischemic myocardium. Using this method makes it possible to identify the "coronary theft" syndrome in experiments on small experimental animals.

The effect of subchronic administration of the nootropics Phenotropil (100 mg/kg/day) on the behavior of CD-1 outbreed mice in the "closed enriched cross maze" test (CECM) was studied. Predominantly, the mouse population was divided into subpopulations according to their values of individual attention index for novel objects in the maze compartments – highly attentive (ED-high) and low attentive (ED-low). It was found that Phenotropil increased the attention index in ED-low, but disimproved it in the ED-high subpopulation, and also changed parameteres of anxiety and locomotor activity; this distinguished it from the more selective effect of Piracetam (200 mg/kg/day). The higher selectivity of Piracetam was also shown in relation to dopamine metabolism processes in the prefrontal cortex: the drug normalized the metabolic turnover of intracellular (DOPAC/DA) as well as extracellular (HVA/DA) dopamine, while Phenotropil influenced on the former only. Thus, positive effect of Piracetam on the attention level in ED-low mice corresponds to the normalization of both indicators of dopamine metabolism in the prefrontal cortex, while Phenotropil showed non-selectivity onto both behavioral and neurochemical parameters. Piracetam and Phenotropil failed to affect the cortical and striatal serotonin metabolism in both subpopulations.

Hemantane (N-adamant-2-yl-hexamethylenimine hydrochloride) is an antiparkinsonian drug with a multicomponent mechanism of action, including a modulating effect on the activity of dopamine and serotonergic mediator systems, a selective inhibitory effect on MAO-B, properties of a low-affinity non-competitive channel blocker of glutamate NMDA receptors, has moderate antiradical and anti-inflammatory activity. The aim of this study was to assess the effect of the neurotoxin MPTP, which is used for modeling of parkinsonian syndrome, and the hemantane on the DNA integrity in the striatum and frontal cortex of the brain of C57BL/6 mice by the DNA comet assay – gel electrophoresis of DNA single cells. Results. In the first experiment, hemantane was administered once a day for 5 days before the MPTP (20 mg/kg, i.p.), then together with MPTP once a day for 5 days. In the second experiment hemantane 10 mg/kg was injected preliminarily for 4 days and 40 minutes before MPTP 30 mg/kg. The obtained results confirm the absence of an effect on DNA of hemantane at a therapeutic dose of 10 mg / kg. In the experimental schemes used, we did not reveal the expected increase in the level of DNA damage under the influence of MPTP, and, accordingly, we were not able to assess the protective effect of hemantane.