四氢小檗碱季铵化合物的合成及其抗心律失常活性

Synthesis and Antiarrhythmic Activity of some Tetrahydroberberine Quaternary Ammonium Compounds

以具心血管活性的四氢小檗碱类生物碱为先导物，结合某些钾通道阻滞剂的结构特征，设计并合成了１４个未见文献报道的四氢小檗碱季铵化合物（Ｉ１～１４），其结构均经波谱分析及元素分析得到确证．初步的药理试验表明：大多数化合物对乌头碱静脉灌注所诱发的大鼠心律失常有不同程度的保护作用，其中化合物（Ｉ６）的活性最强，保护该模型室性早搏、室性心动过速和心脏猝死的ＥＤ５０分别为２．３２ｍｇ／ｋｇ，１．９５ｍｇ／ｋｇ和１．９０ｍｇ／ｋｇ．

On the basis of integration of the structural features of certain potassium channel blockers and by using the berberine alkaloids as leads,14 N substituted phenyloxyalkyl tetrahydro berberine quaternary ammonium compounds(I 1～14 )were designed and synthesized in order to search for novel antiarrhythmic agents.The preliminary pharmacological results in vivo showed that most of these newly synthesized compounds had different degrees of antiarrhythmic activity,including the counteraction to ventricular techycardia(VT),premature ventricular complexes(VP)and sudden cardiac death(SCD).The ED 50 values( iv ) for VP,VT and SCD were 2 32,1 95 and 1 90 mg/kg respectively.The detailed studies of these compounds are under investigation.