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1996 Fiscal Year Final Research Report Summary

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

Research Project

Project/Area Number 06453218
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionOSAKA-CITY UNIVERSITY (1995-1996)
Suntory Institute for Bioorganic Research (1994)

Principal Investigator

OHFUNE Yasufumi  OSAKA CITY UNIVERSITY,FACULTY OF SCIENCE,PROFESSOR, 理学部, 教授 (20142078)

Co-Investigator(Kenkyū-buntansha) SHIMAMOTO Keiko  SUNTORY INSTITUTE FOR BIOORGANIC RESEARCH,RESEARCHER, サントリー生物有機科学研究所, 研究員 (70235638)
Project Period (FY) 1994 – 1996
Keywordsglutamate receptor / 2- (carboxycyclopropyl) glycines / DCG-IV / intramolecular cycloaddition / chiral Rh catalyst / conformational requirements / alpha-substituted glutamate
Research Abstract

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.

  • Research Products

    (10 results)

All Other

All Publications (10 results)

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

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Hashimoto: "Synthesis of Conformationally Restricted Analogs of Kainic" Tetrahedron Letters. 36. 6235-6238 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Shimamoto: "Synthesis and Conformational Andysis of Glntamate Analogs" Journal of Medicinal Chemistry. 39. 407-423 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Shimamoto: "Synthesis of Trans-3-Substituted-CCG-IV Analogs and" Bioorganic and Medicinal Chemistry Letters. 6. 2381-2386 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Ohfune: "Asymmetric Synthesis of 5-and 6-membered Carbocyclic" Chirality. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Hashimoto, O.Yamamoto, M.Horikawa, Y.Ohfune, and H.Shirahama: "Syntheses and Neurobiological Actions of Pyrrolidine-2,3-Dicarboxylic Acids (PRDA). Conformationally Restricted Analogues of L-Aspartate." Bioorg. Med. Chem. Lett.4. 1851-1854 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Shimamoto and Y.Ohfune: "Synthesis and Conformational Analysis of Glutamate Analogs. 2- (2-Carboxy-3-substituted-cyclopropyl) glycines as Useful Probes for Excitatory Amino Acid Receptors." J.Med.Chem.39. 407-423 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 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).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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