本文選題：CB1受體 + 拮抗劑�。� 參考：《廣西醫(yī)科大學(xué)》2014年碩士論文

【摘要】：隨著人們生活水平的改善，肥胖已經(jīng)成為一種全球性流行病。肥胖本身不是病，但由肥胖引起的包括2型糖尿病、冠心病、高血壓、癌癥等以及因體態(tài)引起的心理問題對健康構(gòu)成了很大威脅。良好的飲食習(xí)慣和積極參加運動能在一定程度上減少肥胖，研制抑制肥胖的藥物也是當(dāng)務(wù)之急。到目前為止，西布曲明、利莫那班等治療肥胖的藥物由于嚴(yán)重的中樞副作用退市，市場上僅存的奧利司他療效不顯著且有胃腸道副作用，因此研發(fā)高效、副作用小、臨床耐受性好的新型減肥藥物具有重大意義。 研究證實，大麻素（CB）1型受體的內(nèi)源性配體對食物攝取和能量消耗有雙重調(diào)節(jié)作用。大麻素受體是一種包含7個跨膜區(qū)域的G蛋白偶聯(lián)受體，，可分為CB1和CB2兩個亞型。其中CB1受體主要表達于中樞神經(jīng)系統(tǒng)，在肺、肝臟以及腎臟等外周組織中也有表達，中樞CB1受體主要與抑制食欲、減少攝食有關(guān)，而外周CB1受體主要與調(diào)節(jié)體內(nèi)能量代謝、減輕體重有關(guān)。CB2受體主要分布于免疫組織和細(xì)胞，在中樞神經(jīng)系統(tǒng)中僅有少量表達，主要參與免疫調(diào)節(jié)作用并與神經(jīng)退行性病變有關(guān)。 1994年法國賽諾菲合成實驗室率先研制成功第一個選擇性作用于CB1受體的拮抗劑利莫那班，它對CB1受體的親和力是CB2受體的1000多倍，實驗數(shù)據(jù)表明利莫那班有很好的減肥效果。但是由于其臨床應(yīng)用中的中樞副作用，如抑郁、自殺傾向等，利莫那班于2008年退出市場，作用于中樞CB1受體的拮抗劑的研究也相應(yīng)的終止，但CB1受體作為抗肥胖藥靶點的地位不容置疑。新型CB1抑制劑設(shè)計的關(guān)鍵是找到合理可行的方法克服其中樞副作用的弊端，研發(fā)具有外周選擇性的高效CB1受體拮抗劑成為當(dāng)今抗肥胖研究的新趨勢。TM38837是新一代外周選擇性CB1受體拮抗劑，臨床前研究表明其血腦屏障滲透率低，中樞副作用小，因此新型外周選擇性CB1受體拮抗劑的研究很有潛力，有重大開發(fā)價值。 根據(jù)初步建立的構(gòu)效關(guān)系以及化合物結(jié)構(gòu)與藥代動力學(xué)性質(zhì)之間的關(guān)系，本文以CB1受體拮抗劑TM38837和利莫那班結(jié)構(gòu)類似物為先導(dǎo)化合物，分析了兩類拮抗劑的結(jié)構(gòu)相似性，分別對TM38837和4-甲基-1H-二芳基吡唑類的3位進行結(jié)構(gòu)修飾，設(shè)計了包括兩種結(jié)構(gòu)類型的新化合物，以期獲得高親和力和外周選擇性的CB1受體拮抗劑。 本文共合成了25個目標(biāo)化合物，并采用1H-NMR, MS方法對結(jié)構(gòu)進行了確證。 生物活性評價是采用EGFP-CB1_U2OS細(xì)胞模型對合成的新化合物進行了篩選。初步篩選結(jié)果表明：對TM38837改造得到的第一類化合物抑制活性較低，第二類化合物普遍比第一類化合物抑制活性好，其中BSH-5-10、BSH-5-14和BSH-5-29在1μM時抑制活性與利莫那班相當(dāng)。 通過對化合物結(jié)構(gòu)和生物活性評價結(jié)果分析，初步討論了大麻素1受體拮抗劑的構(gòu)效關(guān)系。兩類目標(biāo)化合物活性的差異表明吡唑環(huán)5位結(jié)構(gòu)對化合物活性有重要影響。TM38837吡唑環(huán)5位引進了極性基團可能對化合物外周選擇性有有幫助，但對活性影響也較大�；钚暂^好的三個化合物的吡唑環(huán)3位都含有苯環(huán)且苯環(huán)和脲基之間有烷基連接，可能與增加吡唑環(huán)3位取代基長度能提高親和力和活性有關(guān)。
[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.
【學(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914

【參考文獻】

相關(guān)期刊論文 前1條

1 嚴(yán)明山,連慕蘭,黃晉生;大麻和大麻受體與免疫應(yīng)答[J];生理科學(xué)進展;2000年03期

本文編號：1949834