1999 Fiscal Year Final Research Report Summary
Structural investiga tions for developing therapeutics of functional disorders due to the sodium channel
| Project/Area Number |
09470493
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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 |
Physical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KURODA Yoshihiro Kyoto University, Graduate School of Pharmaceutical Sciences Associate Professor, 薬学研究科, 助教授 (90093236)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Sodium channel / Inactivation gate / Peptide / Local anesthetics / Dibucaine / Interaction / NMR spectrum / CD spectrum |
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| Research Abstract |
1. The tertiary amine type local anesthetics which possess a charge under physiological conditions interact hydrophobically with the phenylalanine residue in the hydrophobic motif, IMF, of the III-IV linker and also electrostatically with the acidic amino acid residues which locate before and after the IMF motif.
2. At a similar condition as above, benzocaine locates at a polarhead-group region as in the case of the tertiary amine type local anes the tics, but cannot interact with the III-IV linker.
3. The structure at around the IMF motifis generally α-helical. The structure at around the IMF motifis controlled by a hydrogen bonding between the isoleucine in the IMF and the threonine which take a position just after the IMF residues.
4. A pentapeptide KIFMK interacts specifically with the III-IV linker and stabilizes the α-helical structure at around the structure of the IMF motif.
As a therapeutic for paramyotonia congenita (PMC), in which the threonine is mutated into methionine, it is considered that a molecule which can stabilize the α-helical structure formed by the IFMT motifin the wild type sodium can be a good drug.
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