The Gabaa Receptor Body Design Synthesis And Activity Evaluation

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.