乌头碱及其类似物的毒性和对心脏收缩功能的影响

本文报告了乌头碱及其类似物的毒性和对心脏收缩功能的影响,以及这二者与结构之间的关系。结果表明,小鼠ⅳLD₅₀为ACH₅,C-8-OCOCH和OH基的多少和位置以及OH基改变为OCOCH₃基有关。AC,IA,3-AAC,3-AIA,BA和DAIA均引起心律失常;A,PA,TAPA和PAA则无致心律失常作用。实验证明,C-14-OCOC₆H₅是AC致心律失常必不可少的。除AC外的其它8个化合物,在不引起心律失常的剂量下均有降压和抑制心肌收缩力的作用,这种作用无明显的构效关系。对心律无明显影响。

THE TOXICITY OF ACONITINE AND ITS ANALOGUES AND THEIR EFFECTS ON CARDIAC CONTRACTIVE FUNCTION

The present paper reports on the toxicity of aconitine and its nine selected analogs, their cardiac contractive function, and their structure-toxicity and structure-activity relationships.The results showed that the toxicity in terms of iv LD₅₀ of these compounds in mice decreased in the order of aconitine(AC)>indaconitine(IA)=3-acetylaconitine(3-AAC)>3-acetylindaconitine (3-AIA)>benzoylaconine (BA)>diacetylindaconitine (DAIA)>aconine (A)>pseudaconine (PA)>tetraacetylpseudaconine (TAPA)>pentaacetylaconine(PAA). In rats the toxicity in terms of iv absolute lethal dose was found to be in a very slmilar order(AC>3-AAC>IA>3-AIA>BA>DAIA>TAPA>A PA>PAA). Thus, AC appeared as the most toxic one and the other compounds with the corresponding structural modification of AC invariably resulted in a decrease of toxicity. Our findings confirmed the previous general conclusion that the high toxicity of those aconite alkaloids is primarily associated with the presence of C-8-OCOCH₃ and C-14-OCOC₆H₅ in the molecules, while removal of these ester groups by hydrolysis caused sharp decrease in toxicity. It was noted that lowering of toxicity also manifested as a result of changes in the number and position of the free and acetylated hydroxyl groups in the molecules. Those alkaloids containing the C-14-OCOC_{6H5 moiety including AC, IA, 3-AIA, BA and DAIA all induced arrhythmia in rats, while those with deletion of such an ester group, such as A, PA, TAPA and PAA, did not. Thus, C-14-OCOC6H5 is substantiated as an essential functional group in the induction of arrhythmia.All the compounds studied caused a decline in blood pressure and an inhibition of myocardial contraction except aconitine, which showed no such activities before arrhythmia appeared. At present, no generalization could be made about the degree of the effects in relation to structures. Heart rate was not affected in all case by these compounds.The results indicated so far that AC and its related compounds showed no beneficial but harmful effect on the cardial contractive function. Hence, in case should Fu-Zi (aconite) be applied for the treatment of cardiovascular diseases. We would recommend that some new preparations be worked out which are essentially free from the aconitine-type alkaloids. A study towards this end is presently undertaking.}