發(fā)布時間：2018-03-03 13:35

  本文選題：麻醉　切入點：靜脈麻醉藥　出處：《重慶醫(yī)科大學》2016年博士論文　論文類型：學位論文

【摘要】：隨著醫(yī)學技術(shù)的不斷發(fā)展、醫(yī)療水平的日益提升,人類的許多疾病已逐步得到了有效的控制�，F(xiàn)代麻醉學的發(fā)展使得許多原來的手術(shù)禁區(qū)能夠成功地進行,但能夠滿足各種手術(shù),不同人群的要求,使人們達到滿意的鎮(zhèn)靜、鎮(zhèn)痛及肌松效果,仍然是研發(fā)麻醉藥物的熱點和難點。本論文介紹了鎮(zhèn)靜麻醉藥物,尤其是苯二氮卓類藥物的研發(fā)歷程和最新動態(tài)。具有鎮(zhèn)靜催眠功能的苯二氮卓類藥物具有明顯優(yōu)于巴比妥類藥物的特性,但其水溶性差,臨床只能口服給藥。咪達唑侖是第一個用于臨床的苯二氮卓類鎮(zhèn)靜性麻醉藥,其缺點在于其代謝物具有藥理活性,使病人恢復蘇醒的時間延長,因而限制了其用途。為了尋找代謝更為迅速的藥物,藥物化學家受到依托咪酯和瑞芬太尼的啟發(fā),摒棄此前僅從主環(huán)修飾苯二氮卓類藥物的傳統(tǒng)觀念,按照軟藥原理,在苯二氮卓母環(huán)上引入側(cè)鏈,導致了瑞馬唑侖的出現(xiàn),為苯二氮卓類藥物的研發(fā)開創(chuàng)了新的思路。本論文首先對瑞馬唑侖代謝特性進行了深入的研究,發(fā)現(xiàn)瑞馬唑侖側(cè)鏈易代謝,生成唑侖丙酸和甲醇。代謝實驗證實甲醇的次生代謝的產(chǎn)物甲酸可能是造成ICU鎮(zhèn)靜中瑞馬唑侖血藥濃度偏高的重要原因�；谝陨习l(fā)現(xiàn),以瑞馬唑侖為先導化合物,對其側(cè)鏈進行優(yōu)化改造。通過堿解,成酯,成鹽等方法,制備得到7個不同側(cè)鏈取代的衍生化合物,經(jīng)紅外,質(zhì)譜,核磁等確證結(jié)構(gòu)。然后對目標化合物進行了活性篩選,優(yōu)選得到化合物EL-001。在多種動物模型上進行的活性評估結(jié)果顯示,EL-001活性明顯優(yōu)于瑞馬唑侖。代謝實驗結(jié)果表明,EL-001比瑞馬唑侖代謝快且無殘留,進一步驗證了瑞馬唑侖代謝出的甲醇及其次生代謝物甲酸,造成ICU鎮(zhèn)靜中瑞馬唑侖血藥濃度偏高的主要原因,可能是Ono公司退出瑞馬唑侖繼續(xù)開發(fā)的主要原因�？傊�,本論文優(yōu)選得到了成藥性更優(yōu)的化合物EL-001,全面系統(tǒng)的臨床前研究正在進行之中。通過本課題對瑞馬唑侖及其衍生物的研究,評估了瑞馬唑侖及EL-001藥效及代謝物對羧酸酯酶活性的影響,為苯二氮卓類藥物的研發(fā)提供新的思路。
[Abstract]:With the development of medical technology and the improvement of medical level, many diseases of human being have been controlled effectively. The development of modern anesthesiology has enabled many of the original surgical exclusion zones to be successfully carried out. However, it is still a hot and difficult point in the research and development of anesthetic drugs to meet the requirements of various operations and different populations, and to make people achieve satisfactory sedation, analgesia and muscle relaxation effects. In particular, the research and development of benzodiazepines and the latest developments. The benzodiazepines with sedative and hypnotic properties are obviously superior to barbiturates, but their water solubility is poor. Midazolam is the first benzodiazepine sedative anesthetic to be used clinically. Its disadvantage is that its metabolites have pharmacological activities and prolong the recovery time of patients. In order to find drugs that metabolize more quickly, pharmacists, inspired by etomidate and remifentanil, abandoned the traditional idea that benzodiazepines were modified only from the main ring, according to the principle of soft drugs. The introduction of side chain into benzodiazepine ring led to the emergence of ramazolam, which opened up a new idea for the research and development of benzodiazepines. It was found that the side chain of ramazolam was easy to metabolize, resulting in the formation of propionic acid and methanol. The metabolic experiments confirmed that formic acid, the secondary metabolite of methanol, may be an important reason for the high concentration of remiprazolam in ICU sedation. Seven derivatives with different side chains were prepared by alkaline hydrolysis, esterification and salt formation, and the derivatives were synthesized by IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, etc. The structure of the target compound was confirmed by nuclear magnetic field, and then the target compound was screened for activity. The activity evaluation of EL-001 in various animal models showed that the activity of EL-001 was significantly superior to that of ramazolam. The metabolic results showed that EL-001 was metabolized faster than that of ramazolam and had no residue. It is further verified that the methanol and its secondary metabolite formic acid metabolized by Rimazolam lead to the high concentration of remiazolam in ICU sedation, which may be the main reason for Ono to withdraw from the further development of Rimazolam. In this paper, we have obtained a more drug-forming compound EL-001, and a comprehensive and systematic preclinical study is under way. Through this study, we have studied ramazolam and its derivatives. The effects of ramazolam, EL-001 and metabolites on the activity of carboxylate esterase were evaluated, which provided a new idea for the research and development of benzodiazepines.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R914;R96

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本文編號：1561246