1999 Fiscal Year Final Research Report Summary
DESIGN AND SYNTHESIS OF HIGH AFFINITY LIGANDS FOR EXCITATORY AMINO ACID SYNAPSE
| Project/Area Number |
09480143
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | OSAKA-CITY UNIVERSITY |
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Principal Investigator |
OHFUNE Yasufumi OSAKA CITY UNIVERSITY, FACULTY OF SCIENCE, PROFESSOR, 理学部, 教授 (20142078)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMAMOTO Keiko SUNTORY INSTITUTE FOR BLOORGANIC RESEARCH, RESEARCHER, 研究員 (70235638)
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| Project Period (FY) |
1997 – 1999
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| Keywords | glutamate receptor / conformation control / α-substituted-glutamate / transport inhibitor / squaric acid / CCG / DCG-IV / β-benzyloxyaspartate |
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| Research Abstract |
Glutamate receptors and transporters 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 and transporters required a specific conformation of glutamate, but also the analogs are used as tools for the neruopharmacological research.
We have performed (1) the synthesis of new EAA ligands whose conformations are strictly or partically restricted by a carbocycle or an α-substitition of glutamate, (2) the synthesis of β-benzyloxyaspartate (TBOA) and its photoaffinity-labelled derivative as an inhibitor of glutamate transport systems, (3) synthesis of a novel glutamate analog posessing squaric acid moiety which is potent acidic amino acid, and (4) pharmacological characterization of the synthetic glutamate analogs to glutamate receptors and transporters.
Thus, new and sub-type selective agonists for the glutamate receptors have been developed. Optically active L-TBOA was found to be highly effective transport inhibitor and is widely used as a tool to investigate biochemical and biological functions of glutamate transport systems.
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