上海交通大学学报（医学版）

›› 2011, Vol. 31 ›› Issue (7): 909-.doi: 10.3969/j.issn.1674-8115.2011.07.009

• 论著（基础研究） • 上一篇    下一篇

莨菪烷类化合物的合成及其对M3受体的拮抗活性

欧美贤, 史一鸣, 刘慧中, 崔永耀, 朱 亮, 钮因尧, 陈红专, 陆 阳   

  1. 上海交通大学 |医学院药学系, 上海 200025
  • 出版日期:2011-07-28 发布日期:2011-07-27
  • 通讯作者: 钮因尧, 电子信箱: niuyinyao@yahoo.com.cn。
  • 作者简介:欧美贤（1984—）, 女, 硕士生；电子信箱: oumx2007@163.com。
  • 基金资助:

    上海市自然科学基金（10ZR1416900）

Synthesis of tropane compounds and their antagonistic activity to M3 receptors

OU Mei-xian, SHI Yi-ming, LIU Hui-zhong, CUI Yong-yao, ZHU Liang, NIU Yin-yao, CHEN Hong-zhuan, LU Yang   

  1. Department of Pharmacy, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
  • Online:2011-07-28 Published:2011-07-27
  • Supported by:

    Shanghai Natural Science Foundation, 10ZR1416900

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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。

关键词: 莨菪烷, M3受体拮抗剂, 酰化, 离体气管

Abstract:

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.

Key words: tropane, M3 receptor antagonist, acetylation, isolated trachea