| Project/Area Number |
04554021
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
天然物有機化学
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| Research Institution | Hokkaido University |
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Principal Investigator |
SHIRAHAMA Haruhisa Hokkaido University Faculty of Science, Professor, 理学部, 教授 (00000802)
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| Co-Investigator(Kenkyū-buntansha) |
OHFUNE Yasufumi Santory Institute for Bioorganic Research, Chief Investigator, 主任研究員 (20142078)
SHINOZAKI Haruhiko Tokyo Metropolitan Institute of Medicinal Science, Chief Investigator, 薬理研究室長 (20109945)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 1993: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1992: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Keywords | Acromelic acid / Glutamate receptor / Configuration of C_4 side chain in kainoids / 4-phenyl-3-dehydroproline / Carboxycyclopropylglycine / Carboxycyclopentylglycine / Conformational analysis / アクロメリン酸B / 光照射下のジールズアルダー反応 / ピロリジン環の効率的形成 |
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| Research Abstract |
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
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