本文關(guān)鍵詞： κ受體激動劑 “信使”與“位碼”概念 分子模擬 分子對接　出處：《復(fù)旦大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：本課題首先從苯基嗎喃類、嗎啡烴類以及環(huán)氧嗎喃類、芳香乙酰胺類、三環(huán)二萜類和其他結(jié)構(gòu)類型出發(fā),綜述了已經(jīng)發(fā)現(xiàn)的小分子K受體激動劑的多種結(jié)構(gòu)類型,并通過對于K受體結(jié)合能力的高低、活性的強(qiáng)弱,對K受體的選擇性以及構(gòu)效關(guān)系等方面具體闡述了K受體激動劑的研究進(jìn)展。在對此前經(jīng)典K配基梳理、歸納和構(gòu)效關(guān)系總結(jié)的基礎(chǔ)上,從課題前期研究工作發(fā)現(xiàn)的先導(dǎo)結(jié)構(gòu)LQ004C出發(fā),通過經(jīng)典藥物化學(xué)研究方法與計算機(jī)分子模擬技術(shù),系統(tǒng)考察了關(guān)鍵氨基藥效團(tuán)部位的電性、位阻、氫鍵、酸堿性等各種因素對配基活性、亞型選擇性的影響。本課題設(shè)計合成兩個系列共27個目標(biāo)化合物。生物篩選結(jié)果表明在苯胺上引入烷基基團(tuán)對于三種受體的親和性顯著下降,但是引入�；〈鷷r對于K受體的親和力略有上升,其中SLL-039對于K受體的親和力為0.5 nM,K受體相對于μ和δ受體的選擇性為300和600,進(jìn)一步的功能性實驗顯示其為K受體就激動劑,EC50為2.0nM,因此是一個非常有潛力的高選擇性κ配基。
[Abstract]:In this paper, we start with phenyl moans, morphine hydrocarbons, epoxides, aromatic acetamides, tricyclic diterpenoids and other structural types. The various structural types of small molecular K receptor agonists have been reviewed, and the binding ability and activity of K receptor agonists have been studied. The research progress of K receptor agonist was reviewed in detail in the aspects of selectivity and structure-activity relationship of K receptor. Based on the previous classical K ligand combing induction and structure-activity relationship summary. The electrical properties and steric resistance of the key amino pharmacophore sites were systematically investigated by classical pharmacochemical methods and computer molecular simulation techniques based on the leading structure LQ004C found in the previous research work. Hydrogen bonding, acid and alkalinity and other factors on ligand activity. Effects of subtype selectivity. Two series of 27 target compounds were designed and synthesized. The results of biological screening showed that the affinity of introducing alkyl groups to the three receptors on aniline decreased significantly. However, the affinity of SLL-039 to K receptor increased slightly with the introduction of acyl substitution, and the affinity of SLL-039 to K receptor was 0.5 nm. The selectivity of K receptor to 渭 and 未 receptor was 300 and 600 respectively. Further functional experiments showed that the selectivity of K receptor was 2.0 nm. Therefore, it is a highly selective 魏 ligand with great potential.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914;R96

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本文編號：1446789