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 M_3 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 M_3 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 pA_2(M_3)=9.004], and elicited obvious inhibitory effect to NE(inhibition ratio Y_(A2)=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 M_3 receptor antagonistic activity as well as the NE inhibition activity.
引文
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