关附甲素的结构简化物及抗心律失常活性

为寻找活性高、毒副作用小的抗心律失常新药,以关附甲素为先导物进行结构简化,共设计合成了1-苯基-3-烷胺基-1,2-丙二醇类化合物14个和吲哚嗪类化合物9个。对抗氯仿诱发小鼠心律失常试验表明,Ⅰ₁,Ⅰ₂,Ⅰ₃,Ⅰ₇,Ⅰ₈,Ⅰ₁₄和Ⅱ27个化合物有较显著的抗心律失常活性,其中Ⅰ₂,Ⅰ₃,Ⅰ₇和Ⅰ₈抗心律失常活性优于关附甲素。

STRUCTURAL CONGENERS OF GUANFU BASE A AND THEIR ANTIARRHYTHMIC ACTIVITY

Guanfu base A(GFA) is an alkaloid isolated from the root of Aconitum coreanum and is effective in several experimental arrhythmia models. GFA can effectively antagonize aconitine—induced arrhythmia, significantly reduce CaCl₂ — induced incidence of ventricular fibrillation in rats and markedly raise the ventricular fibrillation threshold to electrical stimulation in rabbits and cats. It would be valuable in clinic to treat ventricular fibrillation. Thus, we chose GFA as lead compound for chemical modification.From the view point of stereochemistry, GFA is a rigid structure and can be considered as com posed of two layers. The first layer is a hydrogenated phenanthrene ring; the second is the alkylamino chain containing hydroxy and acetoxy groups. It was speculated that the skeleton of such chain might play as pharmacophore contributing to the biological activity.In order to reduce the size of the molecule and simplify the chemical structure of GFA, the hydrogenated phenanthrene was removed and an aryl residue commonly occurred in the structure of antiarrhythmie agents was introduced. Thus, fourteen derivatives of phenylpropanediolamine were designed and synthesized.There is a hydrogenated indotizine ring in the structure of GFA and a indolizine ring in the structure of class Ⅲ antiarrhythmic agent—butoprizine. By combing the structural feature of GFA with that of butoprizine, nine indolizine derivatives were also designed and synthesized.Screening test of 23 compounds indicated that phenylpropanediolamine derivatives--I₁, I₂, I₃,I₇, I₈, I₁₄, and indolizine derivatives—Ⅱ₂ markedly antagonized chloroform—induced arrhythmias in rats. Among them I₂, I₃, I₇ and I₈, appeared to be more potent than GFA.