新型4-芳香基-1,4二氢吡啶的合成及其局部麻醉效果的研究

发布时间：2018-03-19 12:49

本文选题：4芳香基-1　切入点：4-二氢吡啶衍生物　出处：《南方医科大学》2017年博士论文　论文类型：学位论文

【摘要】：本研究先合成得到四种4芳香基-1,4-二氢吡啶(4-Aryl-1,4-dihydropyridines)化合物,并通过与临床常用局麻药比较,进一步分析其局麻作用和毒性反应,为寻找更好的局麻药提供理论依据和实验基础。方法将100ml乙醇中分次加入1Ommol醋酸铵、1Ommol芳香醛、1Ommol乙酰乙酸乙酯,回流2-3h,然后冷却至室温,合成四种4芳香基-1,4-二氢吡啶化合物,并分析晶体结构。通过建立多种动物模型来分析比较4芳香基-1,4-二氢吡啶与常用局麻药利多卡因、丁卡因、罗哌卡因、布比卡因在表面麻醉、局部浸润麻醉、外周神经阻滞和腰麻的效果。建立大鼠局麻药神经毒性和心脏毒性的模型,分析比较4芳香基-1,4-二氢吡啶化合物与常用局麻药的毒性反应和脂肪乳剂对局麻药毒性反应的逆转作用。结果1.得到四种4芳香基-1,4-二氢吡啶化合物,分别命名为4芳香基-1,4-二氢吡啶化合物1、4芳香基-1,4-二氢吡啶化合物2、4芳香基-1,4-二氢吡啶化合物3、4芳香基-1,4-二氢吡啶化合物4。2.通过动物表面麻醉和局部浸润麻醉模型研究,发现只有4芳香基-1,4-二氢吡啶4具有麻醉作用,表面麻醉效果优于丁卡因、布比卡因和利多卡因(P0.05),通过对角膜的六边形细胞比率(6A)、角膜细胞变异系数(CV)、中央角膜厚度的研究发现4芳香基-1,4-二氢吡啶4对角膜无明显的损伤;局部浸润麻醉效果也优于利多卡因、罗哌卡因、布比卡因(P0.05)。3.分别将4芳香基-1,4-二氢吡啶化合物4和罗哌卡因、布比卡因对大鼠尾局部行神经阻滞,显示4芳香基-1,4-二氢吡啶化合物4的麻醉作用持续时间长,与罗哌卡因、布比卡因神经阻滞组比较,差异具有统计学意义(P0.05)。4.通过建立大鼠腰麻模型,比较4芳香基-1,4-二氢吡啶化合物4、罗哌卡因、布比卡因腰麻的效果,显示4芳香基-1,4-二氢吡啶化合物4镇痛作用和作用时效优于罗哌卡因和布比卡因。与其他两药相较,4芳香基-1,4-二氢吡啶化合物4还能降低腰麻大鼠脑脊液中TNF-α和IL-2的分泌和抑制Caspase3活性,差异具有统计学意义(P0.05)。5.4芳香基-1,4-二氢吡啶化合物4也具有局麻药共同的毒性反应,中毒剂量可致不同程度的心脏毒性或中枢神经毒性。脂肪乳剂能逆转大鼠4芳香基-1,4-二氢吡啶化合物4中毒时的不良心脏反应和惊厥、抽搐等神经毒性反应(P0.05)。结论本研究成功制备的四种4芳香基-1,4-二氢吡啶化合物1～4中,只有4芳香基-1,4-二氢吡啶化合物4具有麻醉活性。其表面麻醉、局部浸润麻醉、神经阻滞麻醉、腰麻效果都好,但是过量使用也同样具有神经和心脏毒性,用脂肪乳剂可逆转4芳香基-1,4-二氢吡啶的心脏和中枢神经毒性。
[Abstract]:This study first synthesized four kinds of 4 aromatic -1,4- two hydrogen pyridine (4-Aryl-1,4-dihydropyridines) compounds, and through comparison and analysis of the clinical commonly used local anesthetics, local anesthetic toxicity and further provide theoretical and experimental basis for finding better local anesthetics. Methods 100ml ethanol fractionated into 1Ommol ammonium acetate, aromatic 1Ommol 1Ommol aldehyde, ethyl acetoacetate, 2-3H reflux, and then cooled to room temperature, synthesis of four kinds of 4 aromatic -1,4- two hydrogen pyridine compounds, and crystal structure analysis. Through the establishment of a variety of animal models to analyze and compare 4 -1,4- two aromatic hydrogen pyridine and commonly used local anesthetic lidocaine, tetracaine, ropivacaine, bupivacaine in surface anesthesia, local infiltration anesthesia, peripheral nerve block and spinal anesthesia effect. To establish the rat neurotoxicity of local anesthetics and heart toxicity model, analysis and comparison of 4 aromatic hydrogen pyridine of two -1,4- Reversal effect of fat emulsion on toxicity and toxic reaction of complexes with commonly used local anesthetics. Results of 1. four 4 -1,4- two aromatic hydrogen pyridine compounds, named 4 aromatic hydrogen pyridine compounds 1,4 -1,4- two -1,4- two aromatic hydrogen pyridine compounds 2,4 -1,4- two aromatic hydrogen pyridine aromatic compounds 3,4 -1,4- two 4.2. hydrogen pyridine compounds through the animal model of surface anesthesia and local infiltration anesthesia, found that only 4 of the aromatic -1,4- two hydrogen pyridine 4 has anesthetic effect, better than tetracaine anesthesia, bupivacaine and lidocaine (P0.05), the percentage of hexagonal cells of the corneal keratocytes (6A), the coefficient of variation (CV). Study on central corneal thickness found no obvious injury in 4 -1,4- two aromatic hydrogen pyridine 4 on the cornea; local anesthesia is better than lidocaine, ropivacaine, bupivacaine (P0.05).3. cloth The 4 aromatic hydrogen pyridine compounds and 4 -1,4- two ropivacaine, bupivacaine on local nerve block of rat tail, 4 -1,4- two aromatic hydrogen pyridine compound anesthetic effect 4 lasted for a long time, and the comparison of ropivacaine, bupivacaine nerve block group, the difference was statistically significant (P0.05.4.) through the establishment of rat spinal anesthesia comparison of 4 models, -1,4- two aromatic hydrogen pyridine compounds 4, ropivacaine, bupivacaine, 4 -1,4- two aromatic hydrogen pyridine compounds showed 4 analgesic effect and time effect is better than that of ropivacaine and bupivacaine. Compared with other two drugs, 4 aromatic -1,4- two hydrogen pyridine compound 4 can reduce the secretion and inhibit the activity of Caspase3 TNF- alpha and IL-2 spinal anesthesia in cerebrospinal fluid of rats, the difference was statistically significant (P0.05).5.4 -1,4- two aromatic hydrogen pyridine compound 4 has the toxicity reaction of local anesthetics in common. Exposure to different degrees can cause cardiac toxicity or neurotoxicity. Fat emulsion can reverse the rat 4 -1,4- two aromatic hydrogen pyridine compounds 4 poisoning adverse cardiac response and convulsions, seizures and other neurotoxic reactions (P0.05). Conclusion: we have successfully prepared four kinds of 4 aromatic -1,4- two hydrogen pyridine compound 1~4. Only 4 -1,4- two aromatic hydrogen pyridine compound 4 has activity. The surface anesthesia anesthesia, local anesthesia, nerve block anesthesia, spinal anesthesia has a good effect, but excessive use also has the nerve and cardiac toxicity, with fat emulsion can be reversed by 4 -1,4- two aromatic hydrogen pyridine heart and neurotoxicity.

【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R914;R965

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