Potassium salts-ligand coordination compounds of magnesium with histidine, adenosine-5'-triphosphate and phosphocreatine, showing a protective effect on the myocardium from ischemic damage

 

(57) Abstract:

Potassium salts-ligand coordination compounds of magnesium with histidine and adenosine-5'-triphosphate of the formula 1 or phosphocreatine formula 2, showing a protective effect on the myocardium from ischemic damage. 3 table.

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The invention relates to pharmacology, in particular ORGANOMETALLIC compounds possessing biological activity, which can find application in drug development for the prevention and treatment of coronary heart disease.

Known for a number of high energy phosphates used for the prevention and treatment of coronary heart disease, for example salts of creatine phosphate (potassium, lithium, calcium, barium, magnesium, iron salt or an organic base), which has biological activity and is used as the active part of the drug product for the treatment of coronary heart disease (GB Pat. N 1185882).

Know the use of disodium salt of adenosine-5'-triphosphate (ATP) for the treatment of circulatory disorders and myocardial protection from ischemic damage (patent USSR N 755201).

However, the known complex in the form of n is cluchuis known biologically active ligands.

The basis of the invention was to develop new coordination compounds of magnesium with histidine and high energy phosphates, showing a protective effect on the myocardium from ischemic damage, which is injected into the connection of another cation would increase the effectiveness of complex biologically active ligands on the myocardium against ischemic heart disease.

The solution provides potassium salt coordination compounds of magnesium with histidine and high energy phosphates of General formula KnMg(His)(MP)mH2O, where His - anion histidine (His-), Mr - anion of high energy phosphate (ATP4-or CRP2-), n = 1 or 3, m = 7, or 8.

The chemical structure of the compounds is expressed by the following formula:

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I Tricolia salt coordination compounds of magnesium with histidine and adenosine-5'-triphosphate

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II - Potassium salt coordination compounds of magnesium with histidine and creatine-phosphate

Coordination compounds of magnesium was prepared in a known manner by dissolving equimolar amounts of magnesium chloride, histidine, ATP or CRP in the minimum amount of water, adding a concentrated solution of bicarbonate isovalerate the precipitate and drying to constant weight at room temperature in air.

The composition of the obtained coordination compounds was confirmed by elemental analysis, thermogravimetry (PL. 1), IR and electronic spectroscopy in the UV region.

Toxicity studies declare coordination compounds showed that I is characterized LD50= 850, and II - LD50= 520 mg/kg

Comparative efficacy of new coordination compounds of magnesium was investigated in an experimental model of acute ischemia (coronary insufficiency) attack, playing on isolated, perfuziruemah on Langendorff the hearts of the rats. The myocardium of animals was perfesional standard solution of Krebs-ringer (pH 7,4), aerated with a gas mixture of Carbogen (95% O2+ 5% CO2). Adequate perfusion and a period of stabilization hearts lasted 30-40 minutes, then perfusion line was switched to a solution containing 0.3 mg/l coordination compounds of N 1 (COP-1) - Na3Mg(His)(ATP)8H2O or coordination compounds of N 2 (CS-2) - K3Mg(His)(ATP)8H2O. After 20 min of perfusion of the hearts with solutions of the investigated complexes were visualized limiting the amount of coronary perfusion by 80 %. The period of ischemia lasted 60 minutes

After 60 min from the start of playback of the heart Guinea is th (intracellular organelles) and study the most important indicators of ion and energy metabolism of the heart muscle in the setting of acute ischemia (table. 2).

In similar conditions was conducted comparative evaluation of coordination compounds of N 3 (CS-3) - Co(CRP) 4H2O and N 4 (CS-4) - KMg(His)(CRP) (H2O (PL. 3) in the same doses that COP-1 and COP-2.

As studies have shown (PL. 2), in the period of adequate perfusion adding KS-2 leads to changes in some indicators of ion and energy metabolism of the heart muscle, which generally indicate a moderate stimulation of redox processes (increased activity --Ketoglutarate-dehydrogenase 15%, dehydrogenase - 7%), improves the function of the ion-transport membrane properties (increase in the activity of Na+, K+-ATP-ASE at 17%, CA2+-binding capacity of the membrane by 9% compared with adequate perfusion. Draws attention to the increase of the power capacity of the heart at the stage of adequate perfusion under the influence of KS-2, as evidenced by the increase in the content of ATP and glycogen, respectively, 16% and 10% compared with the control. In these conditions there is an increase in intracellular potassium and magnesium on 12 and 15% and reducing sodium by 8% compared with the control (table. 2).

Acute myocardial ischemia for 60 minutes PR is at 55 and 60% compared with control. Changes in the bioenergetics of cardiac cells was accompanied by the lipid composition of their membranes (loss of phospholipids by 37%, the accumulation of fatty acids 27%) ion-transport membrane properties (inhibition of Na+, K+-ATP-ASE at 36%, CA2+-binding capacity of the membrane was decreased by 28%). Simultaneously, increased membrane permeability for calcium ions by 85%. The period of ischemia was accompanied by a sharp activation of anaerobic glycolysis and the development of acidosis in the myocardial tissue, which indicated an increase in the concentration of lactic acid in flowing from the heart of the perfusion fluid to the 60-th minute ischemia up to 320% of the original value. In cardiac cells has been a redistribution of electrolytes in the direction of decreasing potassium and magnesium, respectively, at 20 and 24% and increase of sodium and calcium, respectively, 17% and 23% compared with the control (table. 2).

Add the KS-1 for 20 minutes before playing acute ischemia reduced the severity of the above shifts in the direction of normalization of the studied indices. However, most of them by the end of the ischemic period was significantly different from control values due to incomplete recovery and normalization of metabolic processive treatment-and-prophylactic use of COP-2. Reduced activity of Na+, K+-ATP-ases under the influence of the latter was increased by 33% compared to ischemia, while under the influence of KS-1, this figure was up by 12% compared with the ischemic period. The most explicit normalization of the phospholipid and fatty acid composition of membranes was accompanied by a maximum decrease in the membrane permeability to calcium ions under the influence of KS-2 (from 185 to 160% under the influence of KS-1 and up to 128% of the control level under the influence of KS-2). Most pronounced was the activation of oxidative enzymes under the influence of KS-2 (up to 95 and 98% of the control level of the activity of succinate dehydrogenase and-Ketoglutarate-dehydrogenase, respectively). While the least pronounced acidosis in the myocardium (the concentration of lactic acid in the perfusion solution is reduced from 320 to 280% in the case of COP-1 and up to 165% in the case of KS-2 compared with control). The above changes were accompanied by increased levels of energy substrates in the heart (glycogen from 45 to 57% of control with the introduction of COP-1 and up to 89% of control with the introduction of the COP-2; ATP - 40 to 56% of control with the introduction of COP-1 and up to 83% of control with the introduction of the COP-2). More adequate correction of intracellular electrolytes was observed with the introduction of the COP-2 tive compared to KC-1.

As can be seen from the data presented in table 3, adequate perfusion with the addition of COP-4 is a moderate stimulation energy and ion metabolism of cardiac cells, as indicated by activation of Na+, K+-ATP-ases and --ketoglutarates 19 and 13%, respectively, increase in the content of ATP and glycogen in the myocardium at 19 and 15%, respectively, compared to control. In contrast, adequate perfusion with the addition of CS-3 does not cause significant changes of the studied indices.

Changes specific to ischemic period described above. Comparative assessment of the effectiveness of COP-3 and COP-4 shows that more effectively normalizes the metabolism of the latter. It activevideo effect on the Na+, K+ATP-ABC was 13% higher than the COP-3; 21% more effectively normalized membrane permeability for calcium ions under the influence of COP-4 in comparison with the CS-3.

The degree of accumulation of calcium in mitochondria was 16% less under the influence of COP-4 in comparison with the CS-3, which indicates that the normalization processes of biosynthesis of energy in these organelles (excess calcium ions is disconnector oxidative phosphorylation). Activation of oxidative Veritech with COP-4 in comparison with the CS-3. Attracts the greatest degree of membrane lipids, phospholipids and fatty acids in terms of COP-4 in comparison with the CS-3.

The content of ATP and glycogen in cardiac cells was increased due as a COP-3 and COP-4, however, in the case of COP-3 ATP levels were increased by 15% compared with ischemia, and in the case of COP-4, the increase was 38% compared with ischemia. Equally there was a difference in restoring the glycogen content in the myocardium.

Under the influence of COP-4 in contrast to studies using KS-3 showed a maximum increase of intracellular concentrations of potassium and magnesium, while under the influence of COP-3 indicators of ion homeostasis was not significantly different from those of ischemia.

Thus, studies have shown that KS-2 and KS-4, composed of ions of potassium and magnesium, in a certain way coordinated with biologically active ligands, superior in its anti-ischemic and membrane-stabilizing effect connection - KS-1 and KS-3.

Potassium salts-ligand coordination compounds of magnesium with histidine and adenosine-5'-triphosphate of the formula I

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or creativos

 

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