DESIGN AND SYNTHESIS OF HIGH AFFINITY LIGANDS FOR EXCITATORY AMINO ACID RECEPTORS

兴奋性氨基酸受体高亲和力配体的设计与合成

• 批准号: 06453218
• 负责人: OHFUNE Yasufumi
• 金额: $ 4.74万
• 依托单位: OSAKA-CITY UNIVERSITY (1995-1996)Suntory Institute for Bioorganic Research (1994)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06453218/
• 关键词: glutamate receptor; 2- (carboxycyclopropyl) glycines; DCG-IV; intramolecular cycloaddition; chiral Rh catalyst; conformational requirements; alpha-substituted glutamate; 興奮性アミノ酸レセプター; 分子内シクロプロパン化; mGluR2; DCG-IV; CCG; コンフォメーション; 光理化付加; 2-(カル

Glutamate receptors at many synapses in mammalian central nervous systems (CNS) are implicated in the construction of memory and early learnings as well as in the pathogenesis of neuron damage to cause various neuronal diseases. In the recent years, we have studied the conformational role of glutamate when it binds to the receptors through the synthesis of conformationally restricted analogs of glutamate, i.e., L-2-(carboxycyclopropyl) glycines (CCGs) and their 3'-substituted analogs (MCGs and DCG-IV). These works have demonstrated that not only the receptors required a specific conformation of glutamate, but also these analogs are used as tools for the neruopharmacological research. In this project, we have performed (1) improved procedure for the syntheses of various types of MCGs and DCG-IV including photoaffinity labelled analogs based on chiral Rh-catalyzed intramolecular cycloaddition of diazoacetamides, (2) the syntheses of new glutamate analogs with 4 and 6 membered ring analogs, and (3) pharmacological characterization of the synthetic glutamate analogs using several biological preparations. Thus, sub-type selective agonists for the glutamate receptors has been developed and conformational requirements of several types of glutamate receptors in a more presice manner were clearly explained. Works for an introduction of alpha-substituted analogs of glutamate which restricts the rotation of its alpha-position are in progress.

哺乳动物中枢神经系统(CNS)中许多突触上的谷氨酸受体参与记忆和早期学习的构建以及神经元损伤引起的各种神经性疾病的发病机制。近年来，我们通过合成构象受限的谷氨酸类似物，即L-2-(羧基环丙基)甘氨酸(CCGs)及其3‘-取代类似物(MCGs和DCG-IV)，研究了谷氨酸与受体结合时的构象作用。这些工作表明，不仅受体需要特定的谷氨酸构象，而且这些类似物也被用作神经药理学研究的工具。在这个项目中，我们进行了(1)各种类型的MCGs和DCG-IV的合成程序的改进，包括基于手性Rh催化的重氮乙酰胺分子内环加成反应的光亲和标记类似物，(2)新的具有4和6元环类似物的谷氨酸类似物的合成，以及(3)利用几种生物制剂对合成的谷氨酸类似物的药理学表征。因此，谷氨酸受体的亚型选择性激动剂已经被开发出来，并以更预先的方式清楚地解释了几种类型的谷氨酸受体的构象要求。引入谷氨酸的阿尔法取代类似物的工作正在进行中，这种类似物限制了其阿尔法位置的旋转。

项目成果

K.Hashimoto, Y.Ohfune, and H,Shirahama: "Synthesis of Conformationally Restricted Analogs of Kainic Acid. Is the Conformation of the Cis-Substituent of Kainoid Important to Its Neuroexcitatory Activity." Tetrahedron Lett.36. 6235-6238 (1995)

K.Hashimoto、Y.Ohfune 和 H,Shirahama：“红藻氨酸构象限制类似物的合成。红藻氨酸的顺式取代基的构象对其神经兴奋活性很重要。”

Y.Ohfyne, K.Nanba, I.Takada, T.Kan, M.Horikawa, and T.Nakajima: "Asymmetric synthesis of 5-and 6-Membered Carbocyclic Serine Analogs via an Intramolecular Strecker Synthesis." Chirality. (in press).

Y.Ohfyne、K.Nanba、I.Takada、T.Kan、M.Horikawa 和 T.Nakajima：“通过分子内 Strecker 合成不对称合成 5 元和 6 元碳环丝氨酸类似物。”

K.Shimamoto, Y.Shigeri., T.Nakajima, N.Yumoto, S.Yoshikawa, and Y.Ohfune: "Syntheis of Trans-3'-substituted-CCG-IV Analogs and their Characterizataion to Ionotropic Glutamate Receptors." Bioorg. Med. Chem. Left.6. 2381-2386 (1996)

K.Shimamoto、Y.Shigeri.、T.Nakajima、N.Yumoto、S.Yoshikawa 和 Y.Ohfune：“反式 3 取代的 CCG-IV 类似物的合成及其对离子型谷氨酸受体的表征。”

K. Shimamoto: "Synthesis of Trans-3-substituted・CCG IV Analogs and their……" Bioorganic and Medicinal Chemistry Letters. 6. 2381-2386 (1996)

K. Shimamoto：“反式 3 取代·CCG IV 类似物的合成及其……”《生物有机和药物化学快报》6. 2381-2386 (1996)。

K.Hashimoto: "Synthesis and Neurobiological Actions of Pyrrolidine-2,3-" Bioorganic and Medicinal Chemistry Letters. 4. 1851-1854 (1994)

K.Hashimoto：“吡咯烷-2,3-的合成和神经生物学作用”生物有机和药物化学快报。