IR@PKUHSC  > 北京大学药学院
学科主题药物化学
α7烟碱型乙酰胆碱受体激动剂的构效关系研究
李青
2016-05-26
学位类型硕士
导师张亮仁
专业药物化学
授予单位北京大学
授予地点北京大学药学院
学位硕士
关键词精神分裂症 α7烟碱型乙酰胆碱受体 激动剂 中氮茚 构效关系
其他题名Structure-Activity Relationship Studies of α7 Nicotinic Acetylcholine Receptor Agonists
分类号R914.5
页数136
摘要

烟碱型乙酰胆碱受体(nicotinic acetylcholine receptor, nAChR)是一种配体门控型离子通道,属于半胱氨酸环受体超家族,由五个亚单位构成同源或异源五聚体,在中枢和外周神经系统分布广泛。α7烟碱型乙酰胆碱受体(α7 nAChR)是其中的一个亚型,由五个α7亚单位构成同源五聚体,主要分布在大脑皮层和海马区,与认知、学习和记忆功能密切相关。流行病学、基因组学、解剖学和病理学等多方面的研究显示α7 nAChR可以作为精神分裂症认知障碍的潜在治疗靶点。

根据α7 nAChR激动剂的药效团模型和中氮茚类化合物的初步构效关系,本课题设计合成了一系列新的中氮茚类衍生物,通过钯催化偶联等反应在中氮茚环的不同位置引入多种类型的取代基。所有合成的化合物用双电极电压钳的方法进行活性评价。初筛以100 µM乙酰胆碱作为阳性参照,测量10 µM化合物激动起的电流值。若化合物引起的电流值超过参照值的120%,则进行剂量-效应实验,测得化合物的半最大效应浓度(concentration for 50% of maximum effect, EC50)和相对于3 mM乙酰胆碱的最大效应(maximum effect, Emax)。

构效关系研究表明,在中氮茚环的5-位、6-位或8-位引入取代乙炔基的化合物有激动活性,但表现一般(EC50 > 5 μM,Emax < 55%);在中氮茚环5-位或8-位引入取代氨基使得激动活性下降或消失;在中氮茚环6-位和8-位引入小的疏水基团(甲基、乙烯基、环丙基)是一种有效的改造方式,由此得到活性最好的两个化合物24c(EC50 = 1.60 ± 0.19 μM,Emax = 69.0 ± 2.8%)和25b(EC50 = 2.74 ± 0.74 μM,Emax = 81.1 ± 9.3%),相同的取代基在6-位取代的化合物的活性优于8-位取代,而8-位取代的三个化合物的Emax都超过80%。

本课题发现了24c和25b两个活性出众的α7 nAChR激动剂,进一步完善了中氮茚类化合物的构效关系,为新型α7 nAChR激动剂的设计提供了方向。

英文摘要

Nicotinic acetylcholine receptors (nAChR) are members of Cys-loop ligand-gated ion channel (LGIC) superfamily. They are broadly distributed in central nervous system (CNS) and peripheral nervous system (PNS). The α7 nAChR, a homopentamer composed of five α7 subunits, is highly expressed in brain, especially in cerebral cortex and hippocampus that are critical for cognition and memory. Accumulative evidences have been observed that α7 nAChR is implicated in cognitive impairment in schizophrenia and may be a potential therapeutic target.

Pharmacophore models have shown that a cationic center, a hydrogen bond receptor, and a hydrophobic group are generally required for α7 nAChR agonists. We predominantly focused on the hydrophobic group substituted with an indolizine moiety. In this study, a series of indolizine derivatives with various substitutions at different positions on the scaffold have been designed and synthesized to identify novel ive α7 nAChR agonists and investigate the structure-activity relationships (SAR). All compounds were screened and evaluated for their agonist activity using two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes expressing human α7 nAChR.

The results are described as follows. Firstly, alkyne-containing compounds modified at 5-, 6- or 8-position showed agonist activity. The overall bias was towards slightly poorer EC50 ( > 5 μM) and Emax ( < 55%). Secondly, derivatives with amino group at the 5- or 8-position showed poor activity. Thirdly, small hydrophobic groups modified at 6- or 8- position were beneficial to the activity. Compound 24c carrying 6-methylindolizine moiety performed noticeably well with EC50 at 1.60 ± 0.19 µM and Emax at 69.0 ± 2.8%. In addition, 25b with 8-cyclopropyl substitution had significantly higher Emax at 81.1 ± 9.3% and similar EC50 at 2.74 ± 0.74 µM. For EC50, modifications at 6-position were 2~3-fold better than those at 8-position. Modifications on 8-position can significantly improve the Emax ( > 80%).

In this study, a series of α7 nAChR agonists are developed based on indolizine scaffold. Two novel agonists, 24c and 25b, have shown ideal activity in vitro and are worth further evaluation. This study lies a foundation for further identification and validation of α7 nAChR agonists.

语种中文
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文献类型学位论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/149614
专题北京大学药学院
北京大学临床肿瘤学院_重症监护病区
作者单位北京大学药学院
第一作者单位北京大学药学院
推荐引用方式
GB/T 7714
李青. α7烟碱型乙酰胆碱受体激动剂的构效关系研究[D]. 北京大学药学院. 北京大学,2016.
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