莨菪烷类化合物的合成及其对M_3受体的拮抗活性  

Synthesis of tropane compounds and their antagonistic activity to M_3 receptors

作　　者：欧美贤[1] 史一鸣[1] 刘慧中[1] 崔永耀[1] 朱亮[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）》2011年第7期909-912,共4页Journal of Shanghai Jiao tong University:Medical Science

基　　金：上海市自然科学基金(10ZR1416900)~~

摘　　要：目的设计、合成系列莨菪烷类衍生物,测试其对M3受体的拮抗活性,并进行构效研究。方法分别以3α-羟基莨菪烷(D0)、3α-羟基-6β-乙酰氧基莨菪烷(T0)为起始物,通过酰化反应合成3α-酰氧基莨菪烷(D类)和3α-酰氧基-6β-乙酰氧基莨菪烷(T类)。以碘甲烷对D类化合物作进一步烷基化改造,合成N-甲基-3α-酰氧基莨菪烷碘季铵盐(S类)。选取大鼠气管平滑肌(其收缩效应主要由M3受体介导)为测试样本,通过离体组织功能实验,评价合成物对M3受体的拮抗活性。结果制备6个新莨菪烷类化合物,其对M3受体都有明显的拮抗作用。S1对M3受体的拮抗参数pA2值最大,而T2的pA2值最小。结论对莨菪烷母核上的N原子作甲基化改造使化合物的拮抗活性增强,6β位的乙酰氧基使化合物的拮抗活性降低。Objective To design and synthesize a series of tropane derivatives,test their antagonistic activity to M3 receptors,and investigate the structure-activity relationship. Methods 3α-benzoyloxy tropanes(D type) and 3α-benzoyloxy-6β-acetoxy tropanes(T type) were prepared by acetylating 3α-hydroxy-tropane(D0) or 3α-hydroxy-6β-acetoxy tropane(T0) respectively.Quaternary ammonium iodide of N-methyl-3α-benzoyloxy tropane(S type) was acquired by methylating the N atom of azabicyclic ring of D type of compounds with methyl iodide.The antagonistic activity of compounds to M3 receptors on isolated tracheal smooth muscles was evaluated by functional assays. Results Six new tropane compounds were prepared,and obvious antagonistic activity to M3 receptors was elicited.S1 had the highest antagonistic parameter(pA2),while T2 had the lowest one. Conclusion Changing the N atom of azabicyclic ring to quaternary from tertiary through methylation increases the antagonistic activity,while the 6β-acetoxy decreases the activity of compounds.

关 键 词：莨菪烷 M3受体拮抗剂 酰化 离体气管 

分 类 号：R914[医药卫生—药物化学]