1989 Fiscal Year Final Research Report Summary
Physico-chemical studies on the blocking mechanism of glutamate receptors by spider toxin
| Project/Area Number |
63470131
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NAKAJIMA Terumi Fac. Pharm. Sci., Dept. Anal. Chem. Professor, 薬学部, 教授 (50012597)
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| Co-Investigator(Kenkyū-buntansha) |
HAGIWARA Ken'ichi Fac. Pharm. Sci., Dept. Anal. Chem. Associate, 薬学部, 助手 (40192265)
SAITO Hiroshi Fac. Pharm. Sci., Dept. Pharmacol. Professor, 薬学部, 教授 (00012625)
SHUDO Koichi Fac. Pharm. Sci., Dept. Org. Chem. Professor, 薬学部, 教授 (50012612)
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| Project Period (FY) |
1988 – 1989
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| Keywords | spider toxin / polyamine toxin / l-naphthylacetyl spermine / structure-activity relationship / conformational analysis / Zn-complex / NMR / NOESY |
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| Research Abstract |
Spider toxins isolated in the venom of Nephila clavata and N. maculata block the neuromuscular transmission of lobster leg postsynaptically. The chemical feature of the toxins in common, is a linear chain molecule composed of aromatic part connecting polyamine molcule through an asparagine residue by amide bond. Structure-activity relationship of the spider toxin by synthetic approach of analogous materials lead us a conclusion, i.e., bulky hydrophobic moiety connecting with spermine or such kinds of polyamines mimics the action of the spider toxin and maximum blocking activity was observed when the number of basic nitrogen atom in the polyamine part is 3 - 4. Assignment of protons and nuclear Overhduser effect(NOE) measurement by NMR spectroscopy were performed for natural toxins and synthetic analogs. NOE was observed in the middle part of methylene protons in polyamine molecule. Natural toxin and synthetic toxin analog(l-naphthylacetyl spermine) also showed similar conformation by calculation of molecular mechanics. The calculation suggested that the-polyamine part made a loop in the molecule. Resulting from the molecular mechanics calculation, several kinds of azacrown-type analogs were synthesized. Among them, a synthetic compound which possessed dioxo-(14)-ene N_4 markedly enhanced the blocking activity in the presence of Zn ion. Conformational analysis of this compound is now in progress.
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