[The anti-ischemic properties of crown ether derivatives]. / Protivoishemicheskie svoistva proizvodnykh kraun-éfirov.

Experiments on open-chest anaesthetized cats were made to test derivatives of crown ethers, such as benzylase-15-crown-5 and dibenzylase-15-crown-5 for their effects on myocardial ischemia and the functional status of a myocardial ischemic focus in temporary coronary occlusion during coronary spasm induced by dihydroergotamine and during coronary microthrombosis caused by ADP. When intravenously administered in doses of 0.5-15 mg/kg, the tested agents were found to enhance myocardial tolerance to ischemia, depressed ST segment in ischemia induced by coronary occlusion and administration of ATP, and prevented ST-segment depression during coronary spasm.

[The relationship between the magnitude of the negative inotropic action and chemical structure of crown-ether derivatives]. / Zavisimost' mezhdu velichinoi otritsatel'nogo inotropnogo deistviia i khimicheskoi strukturoi proizvodnykh kraun-éfirov.

The relationship between the inotropic effect and chemical structure of 15-crown-5 and 18-crown-6 derivatives was studied in experiments in open-chest anaesthesized cats, by using computer-aided analysis. The findings showed that the 15-crown-5 derivatives produced more pronounced cardiotropic effect and they were less toxic than 18-crown-6 derivatives. Computer-aided analysis revealed pharmacophoric groups which are responsible for cardiotropic (negative inotropic) activity in the series of crown ether derivatives.

[Mechanism of the vascular action of verapamil and a crown ether derivative]. / Izuchenie mekhanizma sosudistogo deistviia verapamila i proizvodnogo kraun-éfirov.

The effects of verapamil and benzyl-aza-15-crown-5 on pressor reactions of blood pressure and perfusion pressure in the femoral artery after administration of noradrenaline, tyramine, angiotensin amide and stimulation of the femoral nerve were studied in acute experiments on anesthetized cats (pentobarbital sodium, 50 mg/kg). Verapamil (0.5 mg/kg) and benzyl-aza-15-crown-5 (9 mg/kg) suppressed pressor reactions to the nerve stimulation and produced no changes at administration of noradrenaline, tyramine and angiotensin amide. One can suggest that the mechanism of the vasodilating action of verapamil and benzyl-aza-15-crown-5 is due to their inhibitory effect on calcium-dependent release of noradrenaline from terminals of the sympathetic nerves. The search of vasodilating agents in the series of crown-ether derivatives is promising.

[Gamma-aminobutyric acid metabolism in the rat brain after administration of nootropic agents]. / Obmen gamma-aminomaslianoi kisloty v golovnom mozge krys v usloviiakh vvedeniia im nootropnykh sredstv.

N,N-bis-pyrrolidonomethyl-diaza - 18-crown-6 and piracetam, which are structural analogues of gamma-aminobutyric acid (GABA) and exhibit nootropic properties, affected the GABA metabolism, the content of total protein, DNA and RNA in rat brain after long-term administration at pharmacologically active doses of 100 mg/kg and 400 mg/kg, respectively. As compared with control values, content of GABA in rat brain was increased by 40% after administration of N,N-bis-pyrrolodonomethyl-diaza-18-crown-6 and by 28%--after treatment with piracetam. At the same time, activity of GABA transaminase was decreased by 49.4% and 39.8%, respectively, while the decarboxylase activity was unaltered.

[Cardio- and hemodynamic effects of a crown ether derivative and an analysis of its cardiotropic action in an experiment]. / Kardio- i gemodinamicheskie éffekty proizvodnogo kraun-éfirov i analiz ego kardiotropnogo deistviia v éksperimente.

The cardio- and hemodynamic effects of the derivative of aza-15-crown-5 was studied in acute experiments on anesthetized (ethaminal sodium, 50 mg/kg) cats. At intravenous administration the compound was found to induce hypotension, to dilate arterial vessels, to exert negative ino- and chronotropic effects, to decrease the cardiac output. The pharmacological analysis suggests that the mechanism of the cardiotropic action of the compound is due to its intervention in calcium ion metabolism.

[Transport and metabolism of a membrane-active complexon in the mouse body]. / Transport i metabolizm membranoaktivnogo kompleksona v organizme myshei.

Two-phase decrease in content of N-(3H-aminoacetyl)-I-aza-4,7,10,11-tetraoxacyclopentadecane hydrochloride (ATCH) and of its metabolites as well as absence of accumulation were observed in mice tissues. Kinetic parameters of 3H-products elimination estimated by means of sequental logarithmation enabled to suggest that ATCH and its free metabolites were intensively involved in biotransformation of molecules. 3H-glycine was found not to be a product of the ATCH metabolism. High and stable level (from 10 min up to 24 hrs) of water soluble and protein-bound derivatives of ATCH were found in mice liver tissue and blood plasma after intravenous administration of the macroheterocycle.

[Kinetics of the excretion of a membrane-active macroheterocycle from the body in mice]. / Kinetika vyvedeniia membranoaktivnogo makrogeterotsikla iz organizma myshei.

The study of the excretion kinetics of N-(3H-aminoacetyl)-I-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride and its metabolites with the mouse urine and feces showed a high relative effectiveness of the urinary excretion (only some 2% of the dose is excreted with the feces). It was also found that there occurs an intensive biotransformation of the compound yielding free and water-soluble metabolites.

[Anti-arrhythmia activity of crown-lactone I and its effect on aconitine-modified sodium channels]. / Antiaritmicheskaia aktivnost' kraun-laktona I i ego deistvie na modifitsirovannye akonitinom natrievye kanaly.

Antiarrhythmic activity of macrocyclic crown-lactone I as well as its effect on biological and model membranes were studied. Crown-lactone displaces the potential dependence of stationary inactivation of TTX-sensible sodium neurons currents towards more negative potentials reducing the modification of those characteristics by aconitine. Proceeding from the comparison between crown-lactone and known antiarrhythmic agents effect on sodium currents a conclusion is made that crown-ethers antiarrhythmic activity cannot be explained by the rhythmoinotropic effect.

[Search for and study of antiarrhythmic substances among crown ethers]. / Poisk i izuchenie antiaritmicheskikh veshchestv v riadu kraun-éfirov.

The authors studied antiarrhythmic properties of macrocyclic polyesters. Some of the esters exhibited antiarrhythmic activity coupled with low toxicity. It was found that antiarrhythmic action of these substances is not mediated via acetylcholine and/or catecholamine system responsible for nervous regulation of the cardiac activity. The compounds under study were found to have marked antifibrillar properties. Experiments on an isolated rat heart demonstrated calcium specificity of the antifibrillar action of cyclolactones. It is assumed that macrocyclic polyesters represent a new class of antiarrhythmic agents having a direct cardiotropic action.

[Effect of the macrocyclic polyether 15-crown-5 on the ionic permeability of excitable membranes]. / Vliianie makrotsiklicheskogo poliéfira 15-kraun-5 na ionnuiu pronitsaemost' vozbudimykh membran.

The macrocyclic polyether 15-crown-5 at a concentration of 5 . 10(-5)-10(-3) M reduced the frequency of the contractions of an isolated rat auricle, increasing the refractory period of the contractions. The polyether lowered the rate of activation of the slow input current of rat spinal ganglionic neurons and blocked the sodium channels of the electroexcitable membrane without disturbing the function of activation and inactivation mechanisms. The compound under study considerably delayed the onset of and decelerated reactivation of the sodium input current. These actions were calcium-dependent, becoming more demonstrable with reduction of Ca2+ concentration outside the cell. 15-Crown-5 interfered with the action of Ca2+ on the lipid bilayer membrane potential. It is assumed that all the effects described are determined by the formation of 15-crown-5-Ca2+ complexes, thereby leading to the impairment of the packing of the membrane lipoprotein matrix.

[Effect of polymethylene- and polyhydroxyethylene-bis-(2-amino-1,3-diazepinium) iodides on cell and model membranes]. / Vliianie polimetilen- i polioksiétilen-bis(2-amino-1,3--diazepinii)-iodidov na kletochnye i model'nye membrany.

The effect of polymethylene- and polyoxyethylene-bis-(2-amino-1, 3-diazepinium) iodides on the membranes of neuromuscular synapsis and mitochondria as on the artificial membranes was studied. The compounds examined were shown to change the amplitude and kinetics of postsynaptic membrane responses to acetylcholine. Inhibition of end plate potentials and oxidative phosphorylation of mitochondria with different derivatives of diazepinium correlated with changes in the surface potential of the artificial phospholipid membrane. It is concluded that the derivatives of diazepinium directly interact with ionic channels of the acetylcholine-activated postsynaptic membrane.

[Effect of macrocyclic amidoesters on membranes]. / Vliianie makrotsiklicheskikh amidoéfirov na membrany.

A comparative analysis of new macrocyclic amidoesters effect on the bimolecular lipid membrane as well as on the electroexcitable membrane of snail isolated neurons was carried out. It was shown that the investigated complexes inducing a small change in lipid bilayer conductivity and some changes in Na-Ca neuron current characteristics produce essential changes of rapid potassium as well as late potassium current properties. It was concluded on the basis of these results and potassium compounds specificity that the investigated complexes interact directly with neuron potassium channels.

[Physiological activity of polymethylene and polyoxyethylene bis-(2-amino-1,3-diazepiniuim) iodides]. / Fiziologicheskaia aktivnost' polimetilen- o pilioksiétilen-bis- -(2-amino-1,3-diazepinii)iodidov.

A study was made of physiological activity of a series of new bisquaternary compounds in which the role of cation heads is played by the residues of 2-amino-1,3-diazepinium. Studies performed on a frog neuromuscular preparation showed that the compounds under test effectively block the responses of the postsynaptic membrane to acetylchinoline. The derivatives of diazepinium have pronounced hypotensive and ganglion-blocking properties. Octamethylene-bis-(2-amino-1,3-diazepinium) iodide that appeared to be the most effective of the compounds under test compares very favourably with benzohexonium. It was found to be 1.5 times more powerful as regards the ganglion-blocking and hypotensive activity.

[Effect of macrocyclic esters on mitochondrial and phosphatidylcholine membranes]. / Vliianie makrotsiklicheskikh slozhnykh efirov na mitokhondrial'nye i fosfatidilkholinovye membrany.

It has been found that some macrocyclic esters have no ionophoric properties, but can block valinomycin-induced potassium transport in mitochondrial membranes and lessen the potassium current induced by valinomycin in phosphatidylcholine bilayers. It has been also discovered that 36-member cyclic esters of succinic acid and propylene glycoles decrease fluorescence of puridine nucleotides in mitochondria and produce a modifying effect on bimolecular phosphatidylcholine membranes in the medium of litium, calcium and magnesium chlorides at unilateral injection. The results obtained suggest that cyclopolyesters under investigation form mixed complexes with the macromolecules in the composition of mitochondrial and phosphatidylcholine membranes with the participation of the integrated ion.