DEVELOPMENT OF POTENT ACTIVE COMPOUNDS WORKING ON NEUROTRANSMIT ORGAN

在神经细胞中，信号是由一种叫做神经递质的化合物传递的。谷氨酸是其中之一，它从前细胞释放并被后细胞的受体接收。这种谷氨酸受体被认为在记忆和学习等重要功能中发挥作用。本课题通过有机合成的方法对该受体的功能进行了研究。1）以21%的总收率合成了丙烯酸B。2）对L-2-（羧基环丙基）甘氨酸（CCG）进行了构象分析。CCGs可以作为清除谷氨酸受体对底物构象需求的探针。合成了几种3 '-取代的CCG类似物，并对其进行了光谱分析和生物活性观察。空间结构 ...更多信息 3）研究了红藻氨酸C_4侧链对π电子平面的构象需求。X射线衍射和光谱研究表明，强活性的kainoids的π-电子平面和吡咯烷环的对角排列。本文合成了π电子平面与吡咯烷环几乎同平面的化合物。它们是3-氮杂-2，8-二羧基-6-甲基双环[3.3.0]辛烷体系，在C_6的外位或端位含有一个双键。这些化合物的生物活性都受到很大的抑制，这表明π电子平面与吡咯烷环之间的对角关系是显示强生物活性的必要条件。4）发展了一种新的芳香类海人藻氨酸的短合成方法。它取决于添加自由基物种产生的甲基丙二酸通过氧化与Mn（III）的4-芳基-3-脱氢脯氨酸。4-芳基-2-羧甲基-4-羟基脯氨酸首先生成内酯，然后通过C_4-羟基的氢解转化为芳基红藻氨酸。5）以3-脱氢谷氨酸为原料，与三亚甲基甲烷加成，合成了4种2-羧基-4-亚甲基环戊基甘氨酸（CPG）的立体异构体。其中，只有CPG-IV的生物活性与红藻氨酸相当。少

Among neurocells signals are transmitted by compounds called neurotransmitters. Glutamic acid is one of them and it is released from a fore-cell are and received by a receptor of a back-cell. This glutamate receptor is believed to play a role in the important functions such as memory and learning. Studies on the function of the receptor through organic synthesis have been achieved in this project.1) Acromelic acid B was synthesized in 21% orverall yield. It was acomplished by the intramolecular Diels-Alder addition of a enolate of an aromatic aldehyde formed by the irradiation of UV light to a doulbe bond conjugated to ester.2) Conformational analysis of L-2-(carboxycyclopropyl)glycine (CCG) was carried out. CCGs would be a probe to clear the conformational demand of the glutamate receptor to the substrate. Several 3'-substituted CCG analogues were synthesized and observed their biological activities and their conformational analysis were carried out spectroscopically. Spatial arrangem … More ent of the functional groups in the substrate was consequently recognized and new agonists were also developed.3) The conformational demand for the pi-electron plane of the C_4 side-chain of kainoid was investigated. X-ray and spectroscopic studies on the strongly active kainoids show the diagonal arrangement of the pi-electron plane and pyrrolidine ring. The compounds whose pi-electron plane has almost the same plane as pyrrolidine ring were synthesized this time. They are 3-aza-2, 8-dicarboxy-6-methylbicyclo[3.3.0] octane system containing a double bond around C_6 in exo or end positions. All of their biological activities depressed very much and it shows that the diagonal relationship between the pi-electron plane and pyrrolidine ring is required to show strong biological activity.4) A short step synthesis of aromatic kainoid was newly developed. It depends on the addition of a radical species generated from methyl malonate by oxidation with Mn(III) to 4-aryl-3-dehydroproline. The lactone from of 4-aryl-2-carboxymethyl-4-hydroxyproline was first produced and it was converted to arylkainoid through hydrogenolysis of C_4-hydroxyl group.5) Four stereoisomers of 2-carboxy-4-methylenecyclopentylglycine (CPG) were synthesized by the addtion of trimethylenemethane to 3-dehydroglutamic acid. Among them, only CPG-IV was biologically active as potent as kainic acid. Less