外周选择性大麻素1型（CB1）受体拮抗剂的设计、合成与生物活性评价

发布时间：2018-05-29 06:24

本文选题：CB1受体 + 拮抗剂　；参考：《广西医科大学》2014年硕士论文

【摘要】：随着人们生活水平的改善，肥胖已经成为一种全球性流行病。肥胖本身不是病，但由肥胖引起的包括2型糖尿病、冠心病、高血压、癌症等以及因体态引起的心理问题对健康构成了很大威胁。良好的饮食习惯和积极参加运动能在一定程度上减少肥胖，研制抑制肥胖的药物也是当务之急。到目前为止，西布曲明、利莫那班等治疗肥胖的药物由于严重的中枢副作用退市，市场上仅存的奥利司他疗效不显著且有胃肠道副作用，因此研发高效、副作用小、临床耐受性好的新型减肥药物具有重大意义。研究证实，大麻素（CB）1型受体的内源性配体对食物摄取和能量消耗有双重调节作用。大麻素受体是一种包含7个跨膜区域的G蛋白偶联受体，，可分为CB1和CB2两个亚型。其中CB1受体主要表达于中枢神经系统，在肺、肝脏以及肾脏等外周组织中也有表达，中枢CB1受体主要与抑制食欲、减少摄食有关，而外周CB1受体主要与调节体内能量代谢、减轻体重有关。CB2受体主要分布于免疫组织和细胞，在中枢神经系统中仅有少量表达，主要参与免疫调节作用并与神经退行性病变有关。 1994年法国赛诺菲合成实验室率先研制成功第一个选择性作用于CB1受体的拮抗剂利莫那班，它对CB1受体的亲和力是CB2受体的1000多倍，实验数据表明利莫那班有很好的减肥效果。但是由于其临床应用中的中枢副作用，如抑郁、自杀倾向等，利莫那班于2008年退出市场，作用于中枢CB1受体的拮抗剂的研究也相应的终止，但CB1受体作为抗肥胖药靶点的地位不容置疑。新型CB1抑制剂设计的关键是找到合理可行的方法克服其中枢副作用的弊端，研发具有外周选择性的高效CB1受体拮抗剂成为当今抗肥胖研究的新趋势。TM38837是新一代外周选择性CB1受体拮抗剂，临床前研究表明其血脑屏障渗透率低，中枢副作用小，因此新型外周选择性CB1受体拮抗剂的研究很有潜力，有重大开发价值。根据初步建立的构效关系以及化合物结构与药代动力学性质之间的关系，本文以CB1受体拮抗剂TM38837和利莫那班结构类似物为先导化合物，分析了两类拮抗剂的结构相似性，分别对TM38837和4-甲基-1H-二芳基吡唑类的3位进行结构修饰，设计了包括两种结构类型的新化合物，以期获得高亲和力和外周选择性的CB1受体拮抗剂。本文共合成了25个目标化合物，并采用1H-NMR, MS方法对结构进行了确证。生物活性评价是采用EGFP-CB1_U2OS细胞模型对合成的新化合物进行了筛选。初步筛选结果表明：对TM38837改造得到的第一类化合物抑制活性较低，第二类化合物普遍比第一类化合物抑制活性好，其中BSH-5-10、BSH-5-14和BSH-5-29在1μM时抑制活性与利莫那班相当。通过对化合物结构和生物活性评价结果分析，初步讨论了大麻素1受体拮抗剂的构效关系。两类目标化合物活性的差异表明吡唑环5位结构对化合物活性有重要影响。TM38837吡唑环5位引进了极性基团可能对化合物外周选择性有有帮助，但对活性影响也较大。活性较好的三个化合物的吡唑环3位都含有苯环且苯环和脲基之间有烷基连接，可能与增加吡唑环3位取代基长度能提高亲和力和活性有关。
[Abstract]:With the improvement of people's living standards, obesity has become a global epidemic. Obesity itself is not a disease, but obesity, including type 2 diabetes, coronary heart disease, high blood pressure, cancer and so on, and the psychological problems caused by the body pose a great threat to health. Good eating habits and active participation in exercise can be to a certain extent. To reduce obesity and develop a drug to inhibit obesity is also a priority. So far, sibutramine, rimonabant, and other drugs for the treatment of obesity due to severe central side effects of the market, the only remaining ollistat on the market is not significant and have gastrointestinal side effects, so the development of efficient, small side effects, good clinical tolerance of new weight loss drugs Things are of great significance.
The study confirmed that the endogenous ligands of the CB type 1 receptor have dual regulation on food intake and energy consumption. The cannabinoid receptor is a G protein coupled receptor containing 7 transmembrane regions, which can be divided into two subtypes of CB1 and CB2. The CB1 receptor is mainly expressed in the central transedian system, in the lung, liver, and kidney and other peripheral tissues. It is also expressed that the central CB1 receptor is mainly related to the inhibition of appetite and feeding, but the peripheral CB1 receptor mainly regulates the energy metabolism in the body, and the weight loss related.CB2 receptors are mainly distributed in the immune tissues and cells, and only a small amount of expression in the central nervous system is involved in the immunoregulation and is related to the neurodegenerative disease.
In 1994, the French Sanofi synthetic laboratory was the first to develop the first selective CB1 receptor antagonist, rimonabant, whose affinity for the CB1 receptor was more than 1000 times the CB2 receptor. The experimental data showed that rimonaban had a good weight loss effect. But because of the central side effects of its clinical application, such as depression, suicide, and so on, Rimonaben quit the market in 2008, and the research on the antagonist of the central CB1 receptor is also terminated, but the status of the CB1 receptor as an anti obesity drug is unquestionable. The key to the design of the new CB1 inhibitor is to find a reasonable and feasible method to overcome the disadvantages of the armature side effects and develop a highly efficient CB1 receptor with peripheral selectivity. Antagonists have become a new trend in the study of anti obesity today.TM38837 is a new generation of peripheral selective CB1 receptor antagonists. Pre clinical research shows that the permeability of blood brain barrier is low and the central side effects are small. Therefore, new peripheral selective CB1 receptor antagonists have great potential and have great potential for development.
According to the preliminarily established structure-activity relationship and the relationship between the compound structure and the pharmacokinetic properties, the structure similarity of the two antagonists was analyzed by using the CB1 receptor antagonist TM38837 and the riimonban structural analogues, and the structure modification of the 3 bits of TM38837 and 4- methyl -1H- two aryl pyrazole, respectively, was set up. Two compounds with different structural types were calculated to obtain CB1 receptor antagonists with high affinity and peripheral selectivity.
25 target compounds were synthesized and confirmed by 1H-NMR and MS methods.
The bioactivity evaluation was screened by EGFP-CB1_U2OS cell model for the new compound. Preliminary screening results showed that the inhibitory activity of the first class compound obtained by TM38837 was low, and the second compounds were generally better than the first class compound, and the inhibitory activity of BSH-5-10, BSH-5-14 and BSH-5-29 at 1 u M It's the same as rimonaban.
The structure-activity relationship of the 1 receptor antagonists of the cannabinoid 1 receptor antagonists was preliminarily discussed by the analysis of the evaluation results of the compound structure and biological activity. The differences in the activity of the two kinds of target compounds showed that the 5 position of the pyrazole ring had an important effect on the activity of the compound, and the 5 position of the pyrazole ring could be helpful to the selectivity of the compound. The activity of the three compounds with better activity has a benzene ring and an alkyl connection between the benzene ring and the urea group, which may be related to the increase of the affinity and activity with the increase of the length of the 3 substituents of pyrazole ring.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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