本文關(guān)鍵詞：GABA_B受體負(fù)向變構(gòu)劑的發(fā)現(xiàn)及其藥理學(xué)機(jī)制研究　出處：《華中科技大學(xué)》2016年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： G蛋白偶聯(lián)受體 GABA_B受體 負(fù)向變構(gòu)劑 藥物篩選 小分子活性探針

【摘要】：γ-氨基丁酸(GABA)是哺乳動(dòng)物中樞神經(jīng)系統(tǒng)中最主要的抑制性神經(jīng)遞質(zhì),它的生理功能主要是通過(guò)離子型的GABAA和GAB Ac以及代謝型的GABAB受體介導(dǎo)的。其中,GABAB受體是屬于C家族G蛋白偶聯(lián)受體(G protein coupled receptor, GPCR),由異源性的GABAB 1 (GB1)和GABAB2 (GB2)兩個(gè)亞基構(gòu)成。GABAB受體在中樞神經(jīng)系統(tǒng)中起著非常重要的作用,已經(jīng)在很多工作中證明了它可以參與了多種神經(jīng)的活動(dòng),其功能異常與痙攣、抑郁、失神性癲癇、焦慮、認(rèn)知障礙和藥物成癮等多種神經(jīng)類(lèi)疾病密切相關(guān)。GABAB受體的激動(dòng)劑baclofe n是目前針對(duì)該受體研發(fā)上市的唯一藥物,能夠通過(guò)舒張松弛肌肉來(lái)改善并治療癲癇。同時(shí),由于變構(gòu)劑研究技術(shù)的發(fā)展,越來(lái)越多的GABAB受體的正向變構(gòu)劑得以發(fā)現(xiàn),并在臨床前研究中表現(xiàn)出對(duì)藥物成癮,焦慮癥等多種疾病的改善效果。GABAB受體的拮抗劑的研究也取得了極大的進(jìn)展,其臨床前研究結(jié)果顯示這些拮抗劑在治療失神性癲癇以及認(rèn)知障礙的潛力。針對(duì)GABAB受體的負(fù)向變構(gòu)劑研發(fā)這些年一直在進(jìn)行,但是目前仍然沒(méi)有化合物發(fā)現(xiàn)的報(bào)道。本課題初為了改善GABAB受體正向變構(gòu)劑效果以及安全性,我們CGP7930為母體改造并合成了一批結(jié)構(gòu)類(lèi)似的小分子化合物。在篩選過(guò)程中,我們意外的發(fā)現(xiàn)了具有負(fù)向變構(gòu)劑活性的化合物,對(duì)化合物結(jié)構(gòu)的優(yōu)化,我們獲得了相對(duì)穩(wěn)定高效的負(fù)向變構(gòu)劑CLH304a。這是世界上首例GABAB受體負(fù)向變構(gòu)劑的發(fā)現(xiàn)報(bào)導(dǎo)。隨后,我們對(duì)負(fù)向變構(gòu)劑抑制各種類(lèi)型激動(dòng)劑以及正向變構(gòu)劑激活GABAB受體的效果進(jìn)行了全面的評(píng)價(jià),并確定了其通過(guò)GB2-HD區(qū)域來(lái)調(diào)控這一抑制過(guò)程的。同樣,除了在人工構(gòu)建的工具體系中,我們?cè)u(píng)價(jià)了負(fù)向變構(gòu)劑對(duì)于原代細(xì)胞內(nèi)天然的GABAB受體信號(hào)通路調(diào)控作用,為針對(duì)神經(jīng)疾病相關(guān)負(fù)向變構(gòu)劑藥物研發(fā)提供能可能性。最后,我們以負(fù)向變構(gòu)劑為活性單元,初步設(shè)計(jì)和開(kāi)發(fā)了針對(duì)GABAB受體小分子活性探針,為進(jìn)一步了解GABAB受體的作用機(jī)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.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R914;R96

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