GABA_B受体负向变构剂的发现及其药理学机制研究

发布时间：2018-01-17 20:30

本文关键词：GABA_B受体负向变构剂的发现及其药理学机制研究　出处：《华中科技大学》2016年博士论文　论文类型：学位论文

【摘要】：γ-氨基丁酸(GABA)是哺乳动物中枢神经系统中最主要的抑制性神经递质,它的生理功能主要是通过离子型的GABAA和GAB Ac以及代谢型的GABAB受体介导的。其中,GABAB受体是属于C家族G蛋白偶联受体(G protein coupled receptor, GPCR),由异源性的GABAB 1 (GB1)和GABAB2 (GB2)两个亚基构成。GABAB受体在中枢神经系统中起着非常重要的作用,已经在很多工作中证明了它可以参与了多种神经的活动,其功能异常与痉挛、抑郁、失神性癫痫、焦虑、认知障碍和药物成瘾等多种神经类疾病密切相关。GABAB受体的激动剂baclofe n是目前针对该受体研发上市的唯一药物,能够通过舒张松弛肌肉来改善并治疗癫痫。同时,由于变构剂研究技术的发展,越来越多的GABAB受体的正向变构剂得以发现,并在临床前研究中表现出对药物成瘾,焦虑症等多种疾病的改善效果。GABAB受体的拮抗剂的研究也取得了极大的进展,其临床前研究结果显示这些拮抗剂在治疗失神性癫痫以及认知障碍的潜力。针对GABAB受体的负向变构剂研发这些年一直在进行,但是目前仍然没有化合物发现的报道。本课题初为了改善GABAB受体正向变构剂效果以及安全性,我们CGP7930为母体改造并合成了一批结构类似的小分子化合物。在筛选过程中,我们意外的发现了具有负向变构剂活性的化合物,对化合物结构的优化,我们获得了相对稳定高效的负向变构剂CLH304a。这是世界上首例GABAB受体负向变构剂的发现报导。随后,我们对负向变构剂抑制各种类型激动剂以及正向变构剂激活GABAB受体的效果进行了全面的评价,并确定了其通过GB2-HD区域来调控这一抑制过程的。同样,除了在人工构建的工具体系中,我们评价了负向变构剂对于原代细胞内天然的GABAB受体信号通路调控作用,为针对神经疾病相关负向变构剂药物研发提供能可能性。最后,我们以负向变构剂为活性单元,初步设计和开发了针对GABAB受体小分子活性探针,为进一步了解GABAB受体的作用机制和生理功能提供了工具。
[Abstract]:Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in mammalian central nervous system (CNS). Its physiological functions are mainly mediated by ionic GABAA and GAB ac and metabolic GABAB receptors. GABAB receptor belongs to G-protein coupled receptor G protein coupled receptor (GPCR) of C family. GABA AB receptor is composed of two subunits of GABAB 1 (GB1) and GABAB2 (GB 2) and plays a very important role in the central nervous system (CNS). It has been demonstrated in many work that it can be involved in a variety of neural activities, with dysfunctional disorders associated with spasms, depression, apocalyptic epilepsy, and anxiety. Cognitive impairment and drug addiction are closely related to the agonist of GABA AB receptor, baclofe n, which is the only drug to be developed and marketed for this receptor. It is possible to improve and treat epilepsy by relaxing and relaxing muscles. At the same time, more and more forward structural agents of GABAB receptor can be found due to the development of the technology of the research on the mutagens. Great progress has also been made in the study of bettering effects of GABA AB receptor antagonists in preclinical studies on drug addiction anxiety disorders and other diseases. The results of its preclinical study show the potential of these antagonists in the treatment of aphasic epilepsy and cognitive impairment. The development of negative structural agents for GABAB receptors has been under way over the years. However, there are still no reports on the discovery of compounds. In order to improve the effect and safety of GABAB receptor forward structuring agents, this study aims at improving the safety of these compounds. We, CGP7930, modified and synthesized a group of small molecular compounds with similar structure. In the process of screening, we accidentally found compounds with negative structuring agent activity. We have obtained a relatively stable and efficient negative structuring agent CLH304a for the optimization of the structure of the compounds. This is the first report of the discovery of GABAB receptor negative structuring agents in the world. We evaluated the effects of negative structuring agents on the activation of GABAB receptors by various types of agonists and forward mutagens. It was determined that it regulates this inhibition process through the GB2-HD region. Again, in addition to the manual tool system. We evaluated the role of negative structuring agents in the regulation of natural GABAB receptor signaling pathway in primary cells, providing the possibility for the development of drugs for neuropathy-related negative structuring agents. Finally. We have designed and developed a small molecular active probe for GABAB receptor with negative structuring agent as the active unit, which provides a tool for further understanding the mechanism and physiological function of GABAB receptor.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914;R96

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