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The relationship between the chemical structure and the antiarrhythmic activity of phenothiazine derivatives--ethacizine and its analogues--was estimated quantitatively by the value of the antiarrhythmic effect on aconitine model in conscious rats. The lengthening of the side chain of nitrogen atom in position 10 of phenothiazine cycle by one methylene group as well as the substitution of demethylamine radical for diethylamine one increased the antiarrhythmic activity; the toxicity of the compound being also increased. Ethacizine was found to possess the highest antiarrhythmic activity and the greatest antiarrhythmic index.

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The antiarrhythmic activity of 20 derivatives of dibenzazepine (the effects on the maximal effective rabbit heart auricle contraction rate, aconitine-induced arrhythmia in rats under or without anesthesia) was studied. It was shown that the most active compounds are those with carbethoxyamine group in position 3 in combination with dimethylamino- or diethylamino-acetyl groups in position 5 of dibenzazepine ring. 5-dimethyl-aminoacetyl-10,11-dihydro-5H-dibenz b, f azepine (GS-015, bonnecor) was selected for the further detailed investigation.

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The antiarrhythmic properties of a new drug bonnecor being a derivative of dibenzazepine were studied on different models of arrhythmias. Bonnecor proved to be effective in the treatment of both atrial and ventricular arrhythmias of various genesis except rhythm disorders induced by ouabain intoxication. The drug was shown to exert a pronounced antifibrillatory effect and to increase the electrical stability of the intact and ischemic myocardium.

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Antiarrhythmic and antifibrillation properties of bonnecor, a derivative of dibenzepin, were studied in comparison with ethmozine, quinidine and novocainamide, using various experimental arrhythmia models. Bonnecor activity was somewhat smaller than that of ethmozine, and much greater than that of quinidine and novocainamide in the mixed atrioventricular arrhythmia model simulated in aconitin-treated rats and the ventricular arrhythmia model simulated by two-degree coronary occlusion in dogs. Intravenous 1 mg/kg and oral 6 mg/kg bonnecor doses prevented ventricular fibrillation caused by acute coronary occlusion in rats, while ethmozine showed no such effect.

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The derivatives of a novel structure series of dibenzazepines dispose of intense antiarrhythmic properties. The relations between structure and effect in comparison with the antiarrhythmically active derivatives of phenothiazine (Ethmozine) are discussed. When substituting the beta-aminopropionyl chain with cyclic residue by means of a dimethylaminoacyl chain there appears a marked antifibrillatory action besides of the intense antiarrhythmic one. The compound 17, the 3-carbethoxyamino-5-dimethylaminoacetyl-dibenzazepine, proved to be the most efficacious compound in the course of the basic screening on two models: action on the effective refractory period in the rabbit's atrium and aconitin-induced arrhythmia in the conscious rat. In comparison with Ethmozin, an antiarrhythmic agent of the phenothiazine type, 17 shows a somewhat lower efficacy in case of i.v. application, but a distinctly intenser one was stated after oral administration. A profound test on the models: two-step coronary ligature in the dog according to Harris and electrofibrillation in the cat's heart, revealed an equally intense antiarrhythmic action but a considerably intenser antifibrillatory one. Therefore the compound 17 (abbreviated designation in the USSR: GS 015 or in the GDR: AWD 19-166) was provided for a thorough pharmacological and toxcological study.

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The intense antifibrillatory and antiarrhythmic actions of GS 015, a derivative of the novel structure series of the 5-(beta-aminoacyl)-3-carbalkoxyamino-iminodibenzyles, are demonstrated on models of myocardial ischaemia: antifibrillatory action on the acute coronary occlusion in the conscious rat (1.0 mg/kg i.v.) and antiarrhythmic action on the two-step coronary ligature in the conscious dog according to Harris (2.0 mg/kg i.v. and 5.0 mg/kg orally). On the strength of the present results it is discussed that GS 015 is first of all suitable for influencing "early arrhythmias" with re-entry mechanism and only in the second line for taking an influence on "late arrhythmias" which arise from the occurrence of ectopic focuses. The substance seems suitable for preventing terminal arrhythmias in patients with ischaemic heart disease as well as for treating arrhythmias in the acute stage of myocardial infarction.

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Study of the relationship between the chemical structure and pharmacological action in the series of dialkylaminoacyl derivatives of phenothiazines made it possible to discover etacyzine (a diethylamine analog of etmozine). Comparison of the pharmacological action of etacyzine with that of etmozine demonstrated that the replacement of the morpholine radical of the side chain of the phenothiazine ring by the diethylamine one leads to the potentiation and increase of the duration of the antiarrhythmic effect, emergence of anti-fibrillary activity, antiischemic properties and to the ability to restrict the size of experimental myocardial infarction.

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The study of the regularities between the chemical structure and pharmacologic action of phenathiazine dialkylaminoacyl derivatives led to the identification and investigation of a new drug called ethacizine-phenothiazin-2-carbethoxyamino-10 (beta-diethylamino-propionyl) hydrochloride. Ethacizine exceeds its structural analogue ethmozin by two times in terms of intensity and by 4-5 times in terms of the duration of antiarrhythmic effect. Ethacizine has marked antianginal properties. It shows a prolonged inhibitory effect on the average elevation of the ST interval at multiple leads of the epicardial electrogram during coronary occlusion, increases the threshold of myocardial ischemia development, and reduces the size of experimental infarction. The combination of potent antiarrhythmic activity, already confirmed by clinical observations, with antianginal properties and a capacity to limit the size of infarction makes in possible to consider ethacizine a promising means for treating coronary heart disease.

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Comparative study of antiarrhythmic properties of marcaine and lidocaine was made on aconitine- and strophanthine-induced experimental arrhythmias and in rhythm disorders induced by electrical stimulation of the ventricles. Marcaine (5 mg/kg) prevented the development of rhythm disorders induced in rats by intravenous injection of aconitine (40 micrograms/kg) and also raised the arrhythmogenic dose of strophanthine (ouabain) in guinea-pigs. Administration of marcaine to anesthetized cats in a dose of 2 mg/kg reduced the assimilation of the rhythm imposed on the heart ventricles at the expense of an increase in the effective refractory period and increased the threshold of electrical fibrillation of the ventricles more noticeably and for a longer time as compared with lidocaine administered in a dose of 5 mg/kg. Marcaine compares very favourably with lidocaine as regards the potency and duration of the antiarrhythmic effect. However, it is inferior to lidocaine from the standpoint of the therapeutic action range. Toxic effects of marcaine do not make clear the prospects of its clinical use as an antiarrhythmic drug. Nevertheless the search of new effective antiarrhythmic drugs among marcaine analogs holds promise.

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Effects of antiarrhythmic drug etmosin and its diethylamine analogue (etmosin DAA) were compared in dogs with the ventricular rhythm disturbances induced by coronary artery ligation according to Harris' method. As demonstrated, both drugs stopped ventricular rhythm disturbances, but etmosin DAA had a more rapid and prolonged effect. Electrophysiological properties of etmosin and etmosin DAA were studied by the method of potential fixation on trabeculae of frog atria. Both drugs proved to reduce rapid sodium inflow, etmosin DAA acting more intensively and longer. Taking into account the high antiarrhythmic activity of etmosin DAA it is believed that this drug had good prospects for further investigation.

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The antiarrhythmic activity of some acyl derivatives of phenothiazine was studied. Ethmozine proved to be the most effective among them. It produced a marked antiarrhythmic effect both in experiments and in the clinic. The effect of ethmozine is similar to that of quinidine, but it has a wider therapeutic range and is less toxic. The drug has practically no effect or arterial pressure, myocardial conduction and myocardial contraction. These properties of ethmozine as well as its ability to prolong the refractory period and reduce myocardial excitability allow it to be recommened for the management of tachyarrhythmic a-rhythmia.

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The effect of nonachlazine, a new antianginal drug, on the rate and the amplitude of contractions of the isolated auricle was studied on guinea pigs and albino rats. Unlike the experiments conducted on intact animals, in the experiments on the isolated auricle nonachlazine proved to decrease the above-mentioned indices. This effect of the drug in the case of the isolated auricle is likely to be due to the ability of nonachlazine to cause a direct effect on the myocardium and the conductive heart system. No specific distinctions in the character of nonachlazine action were revealed.

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The relationship between the chemical structure and antiarrhthmic action in the series of 10-actlaminopropionyl phenothiazine derivatives with different urethan groups in the second position of the phenothiazine cycle (methy, ethyl and isobutyl) was studied. Subject to investigation were also aetmozine isomers containing ethyl-carbaminate in the first, third and fourth position, as well as compounds containing aminopropionyl residues in the tenth and trifluoromethyl group or bromine in the second position. The available data indicated that the antiarrhythmic action of 10-acylamino-derivatives of phenothiazine depends not only on the structure of the side chain and substitution of hydrogen in the second position of the phenothiazine nucleus, but also upon the position of the urethan group in the phenothiazine cycle. Moving ethyl-carbaminate to the first, third and fourth positions results in the fall of the anti-arrhythmic action. The absence of any relation between the length of the urethan radical and the effect produced by the substance was also shown. By substituting the methyl or isobutyl radicals for the ethyl one the antiarrthythmic action of the substances declines.

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