中文摘要：

目的 设计合成丹参素脑靶向衍生物，并研究其在大鼠体外血浆和脑匀浆中的代谢。方法 将四甲基吡嗪及其衍生物作为载体引入丹参素设计脑靶向衍生物，借助计算软件对化合物的脂水分配系数、脑血浓度比、P-糖蛋白亲和力等参数进行预测，筛选出较优化合物DT3进行化学合成;采用HPLC-UV测定DT3及中间产物DT1在大鼠血浆和脑匀浆中的降解情况。结果 制备了两种丹参素-吡嗪酯类衍生物——DT1和DT3;建立了DT3、DT1和羟甲基川芎嗪在大鼠血浆和脑匀浆中同步检测方法;DT3在血浆和脑匀浆中均经历DT3→DT1→活性代谢物过程;DT3在血浆中降解相对于DT1有所减缓，其羟甲基川芎嗪的t1/2分别为1.71和1.68 min;DT3在脑匀浆可快速代谢出羟甲基川芎嗪，且浓度呈现平稳增加，t1/2达222.88 min。结论 本实验设计合成的丹参素-吡嗪酯类衍生物DT3延长了血浆t1/2，同时能在脑匀浆快速降解出活性代谢物。

英文摘要：

OBJECTIVE To design and synthesize brain targeting danshensu （DSS） derivatives and study their metabolism in rat plasma and brain homogenate in vitro. METHODS Tetramethylpyrazine and its derivatives were selected as carriers to design the brain targeting danshen suderivatives. Lipid-water partition coefficient （logP）, brain blood concentration ratio （BB）, and P-glycoprotein affinity of the derivatives were predicted by some calculation softwares and the better compound DT3 was chosen for the next synthesis. The degradation of DT3 and its intermediate DT1 in rat plasma and brain homogenate were measured by HPLC-UV. RESULTS Two danshensu-pyrazine ester derivatives were synthesized, ie DT1 and DT3. A simultaneous determination method of DT3, DT1, and （3,5,6-trimethylpyrazine-2-yl）methanol （TMPM） in rat plasma and brain homogenate was established. The degradation of DT3 in rat plasma and brain homogenate underwent the following processDT3→DT1→the active metabolites of DSS and TMPM.Compared with DT1, the degradation of DT3 in rat plasma slowed down.The half-lives （t1/2） of TMPM were 1.68 and 1.71 min, respectively. Also,DT3 could quickly release the active metabolitein rat brain homogenate, and the concentration of TMPM showed a steady increase with a t1/2 of 222.88 min. CONCLUSION The danshensu-pyrazine ester derivative DT3 has an extended t1/2 in rat plasma, and it can be degraded to active metabolite quickly in rat brain homogenate.