莨菪烷衍生物的合成及其对大鼠气管的拮抗活性和组织选择性  

Synthesis of tropane compounds and their antagonistic activity and tissue selectivity to trachea of rats

作　　者：刘慧中[1] 欧美贤[1] 严忠红[1] 朱亮[1] 崔永耀[1] 钮因尧[1] 陈红专[1] 陆阳[1] 

机构地区：[1]上海交通大学医学院药学系,上海200025

出　　处：《上海交通大学学报（医学版）》2012年第1期27-31,共5页Journal of Shanghai Jiao tong University:Medical Science

基　　金：上海市自然科学基金(10ZR1416900)~~

摘　　要：目的合成系列莨菪烷衍生物,评价其对大鼠气管的拮抗活性及组织选择性(气管/心脏)。方法以3α-羟基-6β-乙酰氧基莨菪烷(A0)为起始物,通过酰化反应合成系列3α-酰氧基-6β-乙酰氧基莨菪烷。分别选取含丰富M2、M3受体并由其介导收缩的大鼠心脏(M2)和气管平滑肌(M3)为测试样本,通过组织功能实验,测试合成物对大鼠离体心脏和气管的拮抗活性。结果制备8个莨菪烷衍生物,A1～A4对心脏和气管有明显拮抗作用,A5～A8对心脏和气管无拮抗活性。A1对气管的拮抗参数pA2值最大(pA2=7.32),且有较高的组织选择性(气管/心脏)(ΔpA2=1.51)。结论减小莨菪烷母核的C-3α位苯环上取代基的体积或增加苯环上π电子云的密度,对提高化合物拮抗气管的活性及组织选择性(气管/心脏)有利。Objective To synthesize a series of tropane derivatives,and investigate their antagonistic activity and tissue selectivity（trachea/heart） to trachea of rats. Methods A series of 3α-acyloxy-6β-acetoxy tropanes were prepared by acetylating 3α-hydroxy-6β-acetoxy tropane（A0）.The antagonistic activities of compounds to muscarinic M2 and M3 receptors on isolated heart and trachea of rats were tested by functional assays respectively. Results Eight tropane compounds were prepared.A1-A4 elicited obvious antagonistic activity to heart and trachea,while A5-A8 had no muscarinic antagonistic activity to heart and trachea.A1 had the highest antagonistic parameter（pA2=7.32） to trachea and higher tissue selectivity（trachea/heart）（ΔpA2=1.51）. Conclusion The antagonistic activity and tissue selectivity（trachea/heart） of compounds to trachea of rats may be improved by decreasing the volume of substituting group connected with phenyl in C-3α position of tropane skeleton or increasing the π-electron density of phenyl ring.

关 键 词：莨菪烷 M3受体拮抗剂 离体气管 选择性 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]