GABAa受体配位体的设计合成和活性评价

【作者】 李果；

【导师】 梁晓天； 尹大力；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2004， 博士

【摘要】 GABAa受体是中枢神经系统主要的抑制性神经递质受体，在中枢神经系统中广泛存在，是一种介导抗焦虑药物、镇静药物、抗惊厥药物、癫痫和失忆活动的多功能药物作用靶标。比扣扣灵(Bicuculline，BIC)是GABAa受体的经典竞争性拮抗剂，它与GABA识别位点高亲和力结合，选择性阻断GABAa受体，故长期以来一直把它作为识别GABAa受体的工具药。本论文采用分子剖析的方法对其结构和活性的关系进行研究，根据药效团将比扣扣灵分为四氢异喹啉和苯酞两个结构，对这两个结构区域进行活性以及毒性的生物学的测定，探讨构效关系并找出活性结构域和药效团。基于结构剖析结果，本论文进行了以下合成工作：一、合成了一系列苯酞类衍生物：(一)尝试多种方法和路线合成了苯酞3位延伸出一个碳原子的11个目标化合物。(二)尝试多种方法和路线合成了苯酞3位延伸出两个碳原子的35个目标化合物。(三)尝试多种方法和路线合成了苯酞3位侧链为酯基的8个目标化合物。二、合成了五类苯环上带不同取代基的苯酞及其衍生物。三、合成了7个苯并四氢呋喃类目标化合物。四、对新发现的缩合反应进行了考察和探索。论文共合成了113个苯酞类中间体及目标化合物。其中66个目标化合物，全部目标化合物及部分性质稳定的中间体都通过核磁、质谱、红外等方法确证，部分目标化合物通过元素分析、高分辨质谱等方法确证。对3位延伸出一个和两个碳原子的胺类衍生物的质谱裂解规律进行了探讨。对新发现的缩合反应的机理和可能的应用范围进行了考察和探索。对部分目标化合物的活性结果进行了活性测定和初步评价。更多还原

【Abstract】 GABAa is a receptor of inhibitory transmitterγ-butyric acid(GABA), in the central nervous system (CNS) which distributes widely. GABAa receptors are the targets associated with various disorders in central nervous system such as convulsion, anxiety, epilepsy, losing of memory etc. Bicuculline is a classical competitive antagonist of GABAa receptor. It selectively binds to GABAa receptor and blocks the inhibitory effect of GABA. It has been used as a tool agent in pharmacology to indentify GABAa receptor for a long time. To explore structure activity relationship, the s tructure o f b icuculline w as d issected i nto t etrahydroisoquinoline a nd p hthalide 1 OOd on the hypothesis that GABAa binding domain of the molecule is between the groups of N and C=O. Thus, the designed molecules were synthesized and their biological activity were tested to learn the structure activity relationship of such molecules.A series of derivatives were synthesized starting from phthalide and 2-carboxybenzaldehyde.1. Through the Henry reaction between 3-hydroxyphthalide and nitromethane, 3-nitromethyl phthalide was prepared. Then, the derivatives of 3-substituted (aminomethyl) phthalides was synthesized by hydrogenation of 3-nitromethyl phthalide and the Reductive Alkylation of 3-aminomethylphthalide.2. Through the Knoevenagel reaction of 2-carboxybenzaldehyde and malonic acid, 2-phthalidylacetic acid was prepared. Then 2-Phthalidylacetic amides was synthesized through the condensation of 2-phthalidylacetic acid with amines. Some of derivatives of 3-substituted (aminoethyl)phthalides were obtained by reduction of derivatives of 3-phthalidylacetic amides by borane-methyl sulfide complex in THF. Other 3-(2-aminoethyl)substituted phthalide’s derivatives were synthesized by Reductive Alkylation of 3-aminoethylphthalide, which was obtained by hydrogenation of 3-acetonitrile phthalide. 3-Acetonitrile phthalide was synthesized through the reaction of Wittig reagent of chloroacetonitrile with 2-carboxybenzaldehyde.3. The derivatives of N-alkyl-3-substituted (aminoethyl)phthalans were synthesized by several synthetic methods, including direct reduction of 3-substituted (aminoalkyl)phthalides, and Reductive Alkylation of 3-aminomethylphthalan, which was produced from 3-acetonitrile phthalide by reduction with Borane/THF.4. Five phenyl substituted phthalide derivatives were prepared through Vilsmeier reaction, Chloromethylation reaction, and so on.Totally 113 compounds were synthesized, 66 of which are targeted molecules. All structures of them were validated by NMR, MS, EA or HRMS.A new condensation reaction was discovered between 3-ethoxylphthalide and Diethylmalonate. The mechanism and scope of this new reaction were investigated.1. We suppose that 3-ethoxy-phthalide in sodium/ethanol ethoxide through Ring-Chain Tautomerism changed into its open-chain isomer and the latter immediately underwent aldol condensation with the carbanion of diethylmalonate, followed by simultaneous cyclization to afford compound 8. A direct proof is that condensation of 7 with diethylmalonate can also give 8, But the yield is much lower probably because the instability of 7 under basic condition.2. The condensation of 3-Ethoxyphthalide was also conducted with ethyl acetoacetate and ethyl cyanoacetate. The reaction with ethyl cyanoacetate gave predicted product in 82％yield. But reaction with ethyl acetoacetate failed. On the other hand when semi-ketal lactone, compound 106, was condensed with diethylmalonate under similar conditions compound 108 was obtained in 89％yield. In summary, we have found that semi-acetal lactone 6 and semi-ketal lactone 107 can undergo aldol type condesation with some carbanions. This method is convient and may be useful for the synthesis of phthalides with 3-functionalized substitutents which can not be obtained by the conventional Gabriel method.更多还原