抗心律失常药物的研究Ⅲ．关附甲素酯类化合物的合成及抗心律失常活性研究

STUDIES ON ANTIARRHYTHMIC AGENTS Ⅲ. SYNTHESIS OF GUANFU BASE A ESTER DERIVATIVES AND THEIR ANTIARRHYTHMIC ACT IVITY

以关附甲素和关附醇胺为原料，设计合成了６个关附甲素酯类化合物。药效实验结果表明，化合物Ⅰ、Ⅱ、Ⅲ和Ⅵ对乌头碱诱发大鼠心律失常具有明显的保护作用，其中化合物Ⅰ、Ⅱ和Ⅵ的生物活性优于关附甲素。构效关系研究结果表明。

Guanfu base A ( GFA ) , Guanfu base B ( GFB ) and Guanfu base C ( GFC ) , alkaloids isolated from the root of Aconitum Coreanum, are effective in several experimental arrhythmic models and their antiarrhythmic activity were GFC>GFA>GFB. According to the MM2 program calculation and effect of hydrophobic property on antiarrhythmic activity, several acyl chlorides with different hydrophobic surface area were selected, and six compounds were prepared by reaction of GFA or Guanfu alcoholamine ( AA ) with acyl chloride. Their structures were confirmed by IR,MS and elemental analysis. Preliminary pharmacological study showed that Ⅰ ,Ⅱ,Ⅲ and Ⅵ were effective against aconitineinduced arrhythmia in rats, and Ⅰ , Ⅱ, and Ⅵ were more potent, less toxic and showed longer duration of antiarrhythmic action in rats than GFA. Structure activity relationship study indicated that their antiarrhythmic activities have good correlation with the ratio of molecular hydrophobic surface area to molecular hydrophilic surface area in a nonlinear mode.