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苯并中氮茚甲酰胺衍生物的设计、合成及构效关系研究

Study on the Design, Synthesis and SAR of Benzo-Indolizine Derivatives

中文摘要英文摘要

目的:本文在已知α7 nAChR激动剂药效团特征的基础上,通过改变疏水片段π体系的大小,来考察目标化合物对α7 nAChR激动效应的影响,从而设计并合成了一系列苯并中氮茚甲酰胺衍生物,通过其构效关系的研究,为获得潜在的α7 nAChR小分子激动剂提供理论依据。方法:本文选择了价格低廉的取代苯胺原料,设计了一条成熟的合成路线,得到了25个化合物及进行定性和定量的激动活性评价,并总结了初步的构效关系。结果:多数化合物Emax值要高于阳性参照物,个别化合物表现出与阳性参照物相当的EC50值。初步的构效关系表明激动剂与靶点的疏水相互作用对于α7 nAChR激动效应是至关重要的。

Objectives: Based on the known pharmacophore properties of α7 nAChR agonists, to design a series of benzo-indolizine derivatives by changing π system of hydrophobic segment so as to improve agonistic level. Methods: By utilization of many cheap materials, several straightforward and mature routes were designed and 25 target compounds were synthesized for subsequent activity assay. Results: Most of compounds show obvious agonistic effect at 10 μM and some of them give strong agonistic activity, i.e. 9a, 9b, 9e, 9f, 10, 14d and 17f, especially 10 with an EC50 value at 0.91 μM. In addition, most of targets show higher efficacy (Emax) than control EVP-6124. Investigation of SAR provides some insights for the development of novel active agonist of α7 nAChR.

张桂森、薛雨、李青、杨洮乙、张亮仁、王克威

药学基础医学化学

药物化学精神分裂症认知障碍α7 nAChR激动剂构效关系

Medicinal chemistrySchizophreniaCognitive impairmentα7 nAChRAgonistsSAR

张桂森,薛雨,李青,杨洮乙,张亮仁,王克威.苯并中氮茚甲酰胺衍生物的设计、合成及构效关系研究[EB/OL].(2017-05-05)[2025-08-23].http://www.paper.edu.cn/releasepaper/content/201705-402.点此复制

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