Kaverina N V, Senova Z P, Lyskovzev V V, Demina L M, Grizenko A N, Skoldinov A P, Femmer K, Poppe H, Stark A, Wunderlich H
Pharmazie. 1985 Dec;40(12):830-2.
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.
一类新型二苯并氮杂卓结构系列衍生物具有强烈的抗心律失常特性。文中讨论了这些衍生物的结构与效应之间的关系，并与抗心律失常活性的吩噻嗪衍生物（乙吗噻嗪）进行了比较。当用二甲基氨基酰基链取代β-氨基丙酰基链上的环状残基时，除了强烈的抗心律失常作用外，还出现了明显的抗纤颤作用。在对两种模型进行的基础筛选过程中，化合物17（3-乙氧羰基氨基-5-二甲基氨基乙酰基-二苯并氮杂卓）被证明是最有效的化合物：对兔心房有效不应期的作用以及对清醒大鼠乌头碱诱发的心律失常的作用。与吩噻嗪类抗心律失常药物乙吗噻嗪相比，化合物17静脉注射时疗效略低，但口服后疗效明显增强。在以下模型上进行的深入试验：根据哈里斯法对犬进行两步冠状动脉结扎以及对猫心脏进行电除颤，结果显示其抗心律失常作用同样强烈，但抗纤颤作用明显更强。因此，化合物17（苏联的缩写名称：GS 015或民主德国的缩写名称：AWD 19-166）被用于全面的药理和毒理学研究。
