α1-肾上腺素能受体小分子荧光探针的设计、合成及活性研究

发布时间：2018-03-17 23:35

本文选题：α_1-肾上腺素能受体　切入点：小分子荧光探针　出处：《山东大学》2014年硕士论文　论文类型：学位论文

【摘要】：α1-肾上腺素能受体(α1-adrenergic receptors,α1-AR)是G蛋白偶联受体家族的一种,广泛的分布于人体的各种细胞、组织和器官中,是交感神经系统的重要介质,可参与体内很多重要的生理反应,并与多种疾病的发生有着密切的关系,例如高血压和前列腺疾病等。因此,加强对α1-肾上腺素能受体的药理学及病理学特征的研究对于多种疾病的发病机制研究、临床诊断和治疗具有重要的意义。本论文是基于肾上腺素能α1受体的小分子荧光探针的合成及活性研究,主要包括五部分：一、前言；二、小分子荧光探针的设计；三、荧光探针的合成；四、荧光探针的活性研究；五、总结与展望。论文的第一部分主要介绍α1-肾上腺素能受体概况及α1-肾上腺素能受体的研究概况,小分子荧光探针的设计原理、荧光强度的影响因素及应用前景。论文的第二部分是设计基于α1-肾上腺素能受体的小分子荧光探针,在课题组前期工作的基础上,在已有α1-肾上腺素能受体拮抗剂的结构基础上,选取苯基哌嗪和喹唑啉母核为药效团,荧光素和萘二酰亚胺母核为荧光团,通过连接基团相连,设计α1-肾上腺素能受体的小分子荧光探针。论文的第三部分通过有机化学方法,如Claisen重排、Mannich反应、Gabriel反应和亲核加成与消除等反应合成a1-肾上腺素能受体的荧光探针。论文的第四部分为活性研究,对合成的荧光探针分别进行了光学性质研究、a1-肾上腺素能受体各亚型亲和力测试、细胞荧光成像和细胞毒性的研究。结果显示所合成的荧光探针有良好的光学性质、高度的亲和力、良好的细胞荧光成像潜力和较低的细胞毒性。最后,基于本论文的研究,我们合成了能在细胞水平对a1-肾上腺素能受体进行荧光标记的小分子荧光探针,也为今后此类荧光探针的进一步结构改造提供依据,希望找到理想的基于α1-肾上腺素能受体的荧光探针。此外,鉴于合成的探针分子对α1-肾上腺素能受体各亚型的高度亲和力,也可利用荧光学方法,将此类探针作为底物,建立αl-肾上腺素能受体拮抗剂的筛选方法,由于该方法简单、方便,进而可以取代目前广泛使用的放射性配基结合实验法。
[Abstract]:伪 1-adrenergic receptors (伪 1-ARs) are a family of G protein-coupled receptors. They are widely distributed in various cells, tissues and organs of the human body. They are important mediators of the sympathetic nervous system and can participate in many important physiological responses in the body. It is closely related to the occurrence of many diseases, such as hypertension and prostatic diseases. Therefore, the study of pharmacological and pathological characteristics of 伪 1-adrenergic receptor has been strengthened to study the pathogenesis of many diseases. Clinical diagnosis and treatment are of great significance. This thesis is about the synthesis and activity study of small molecule fluorescence probe based on adrenergic 伪 1 receptor. It includes five parts: first, foreword; second, design of small molecule fluorescence probe; third, synthesis of fluorescent probe; fourth, Study on the activity of fluorescent probe. Fifth, summary and prospect. The first part of the thesis mainly introduces the general situation of 伪 1-adrenergic receptor and the research of 伪 1-adrenergic receptor, the design principle of small molecular fluorescence probe, the influencing factors of fluorescence intensity and the prospect of application. The second part of the thesis is to design a small molecular fluorescence probe based on 伪 1-adrenergic receptor. Based on the previous work of the research group, the structure of 伪 1-adrenergic receptor antagonist has been established. Phenylpiperazine and quinazoline mother nuclei were selected as pharmacophore, fluorescein and naphthalenediimide mother nuclei were selected as fluorescence groups, and small molecular fluorescence probes of 伪 1-adrenoceptor were designed by connecting groups. In the third part of the thesis, the fluorescence probe of a 1-adrenergic receptor was synthesized by organic chemistry, such as Claisen rearrangement Mannich reaction and nucleophilic addition and elimination. The 4th part of the thesis is the activity study. The optical properties of the synthesized fluorescent probe were studied and the affinity of each subtype of A1-adrenergic receptor was tested. The results show that the synthesized fluorescent probe has good optical properties, high affinity, good cell fluorescence imaging potential and low cytotoxicity. Finally, based on the research in this thesis, we synthesized small molecular fluorescent probes that can label a 1-adrenergic receptor at the cell level, and provided the basis for further structural modification of such fluorescent probes in the future. Desiring to find an ideal fluorescent probe based on 伪 _ 1-adrenergic receptors. In addition, in view of the high affinity of the synthesized probe molecules to various subtypes of 伪 _ 1-adrenergic receptors, such probes can also be used as substrates by fluorescence methods, A screening method for 伪 -adrenergic receptor antagonists was established. Because of its simplicity and convenience, it can replace the widely used method of radioligand binding experiment.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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