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pA_2(M_3)=9.004;并且A2对NE具有较明显的抑制作用(抑制率Y_(A2)=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M_3受体、抑制NE的活性。
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.
出处
《上海交通大学学报（医学版）》
CSCD
北大核心
2017年第8期1059-1063,共5页
Journal of Shanghai Jiao tong University:Medical Science
基金
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)~~
