基于优势结构的κ配基设计、合成及生物活性研究
发布时间:2018-01-20 04:10
本文关键词: κ受体激动剂 “信使”与“位码”概念 分子模拟 分子对接 出处:《复旦大学》2014年硕士论文 论文类型:学位论文
【摘要】:本课题首先从苯基吗喃类、吗啡烃类以及环氧吗喃类、芳香乙酰胺类、三环二萜类和其他结构类型出发,综述了已经发现的小分子K受体激动剂的多种结构类型,并通过对于K受体结合能力的高低、活性的强弱,对K受体的选择性以及构效关系等方面具体阐述了K受体激动剂的研究进展。在对此前经典K配基梳理、归纳和构效关系总结的基础上,从课题前期研究工作发现的先导结构LQ004C出发,通过经典药物化学研究方法与计算机分子模拟技术,系统考察了关键氨基药效团部位的电性、位阻、氢键、酸碱性等各种因素对配基活性、亚型选择性的影响。本课题设计合成两个系列共27个目标化合物。生物筛选结果表明在苯胺上引入烷基基团对于三种受体的亲和性显著下降,但是引入酰基取代时对于K受体的亲和力略有上升,其中SLL-039对于K受体的亲和力为0.5 nM,K受体相对于μ和δ受体的选择性为300和600,进一步的功能性实验显示其为K受体就激动剂,EC50为2.0nM,因此是一个非常有潜力的高选择性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.
【学位授予单位】:复旦大学
【学位级别】:硕士
【学位授予年份】:2014
【分类号】:R914;R96
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