上海交通大学学报（医学版）

上海交通大学学报（医学版）

• 论著（基础研究） • 上一篇    下一篇

莨菪烷类化合物拮抗M3 受体、抑制中性粒细胞弹性蛋白酶活性的研究

蔡玉兴1，刘慧中1，胡优敏2，张建华3，金玉杰1，李宁1，钮因尧3   

  1. 上海交通大学 基础医学院1. 实验教学中心化学生物学实验室；2. 实验教学中心功能学实验室；3. 化学教研室，上海 200025
  • 出版日期:2017-08-28 发布日期:2017-09-28
  • 通讯作者: 钮因尧，电子信箱：niuyinyao@aliyun.com
  • 作者简介:蔡玉兴（1984—），男，实验师，硕士生；电子信箱：xcallenn@126.com
  • 基金资助:
    上海市卫生和计划生育委员会科研课题（201440575）；上海交通大学医学院科技基金（14XJ10006）

Study of antagonistic activity against M3 receptor and inhibition activity to neutrophil elastase of tropane compounds#br#

CAI Yu-xing1, LIU Hui-zhong1, HU You-min2, ZHANG Jian-hua3, JIN Yu-jie1, LI Ning1, NIU Yin-yao3   

  1. 1. Chemicobiological Laboratory, Experiment-teaching Center, 2. Functional Training Laboratory, Experiment-teaching Center, 3. Department of Chemistry, Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China
  • Online:2017-08-28 Published:2017-09-28
  • Supported by:
    Scientific Research Project of Shanghai Municipal Health and Family Planning Commission, 201440575；Science and Technology Fund of Shanghai Jiao Tong University School of Medicine, 14XJ10006

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摘要： 目的 · 设计、合成 5 个新莨菪烷类化合物，测试其拮抗 M3 受体、抑制中性粒细胞弹性蛋白酶（NE）的活性，初步分析 2 种 活性的构效关系。方法 · 对莨菪烷母核的C-3α 位、N 原子进行结构改造，以3α- 羟基莨菪烷（A0）为起始物，合成A1 ～ A3、 B1、C1。选取豚鼠气道环为测试样本，通过离体组织功能实验，测试目标物对 M3 受体的拮抗活性。利用 NE 催化底物 PGlu-Pro-ValPNA 的水解反应，测定有色产物硝基苯胺（PNA）的吸光度值[D(405 nm)]，获得目标物对NE 的抑制活性。结果 · 5 个新化合物对 M3 受体都具有较强的拮抗作用，其中 A2 的拮抗活性最大，拮抗参数 pA2(M3)=9.004；并且 A2 对 NE 具有较明显的抑制作用（抑制率 YA2=20.29%）。 结论 · 在莨菪烷母核的 C-3α 位引入强吸电子基团磺酰基和大体积疏水基团时，有利于同时提高化合物拮抗 M3 受体、 抑制 NE 的活性。

关键词: &ensp, 莨菪烷, 毒蕈碱型胆碱能受体, M3 受体拮抗剂, 中性粒细胞弹性蛋白酶, 构效关系

Abstract:

 Objective · To design and synthesize five new tropane compounds， and test their antagonistic activity against M3 receptor and inhibition activity to neutrophil elastase (NE), of which the structure-activity relationship were preliminarily investigated.  Methods · The five compounds, A1-A3, B1 and C1, were prepared with 3α-hydroxy-tropane (A0) as the starting material by modifying the structure in C-3α position and N atom on the tropane skeleton. The antagonistic activity of the compounds to muscarinic M3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The hydrolysis of PGlu-Pro-Val-PNA as substrate was catalyzed by NE to get colorful nitroaniline (PNA). The NE inhibition activity of the tropane compounds was obtained by determining the absorbance [(D(405 nm)] of PNA.  Results · The five new tropane compounds generated strong antagonistic activity against M3 receptors. Among them, A2 had the greatest activity [antagonistic parameter pA2(M3)=9.004], and elicited obvious inhibitory effect to NE (inhibition ratio YA2=20.29%).  Conclusion · Introducing strong electron-attraction group, such as sulfuryl and hydrophobic group with large volume into C-3α position on the tropane skeleton can improve the M3 receptor antagonistic activity as well as the NE inhibition activity.

Key words: tropane, muscarinic cholinergic receptors, M3 receptor antagonist, neutrophil elastase, structure-activity relationship