Structural investiga tions for developing therapeutics of functional disorders due to the sodium channel

1. 叔胺型局部麻醉药在生理条件下具有电荷，与III-IV连接体的疏水基序IMF中的苯丙氨酸残基疏水相互作用，也与IMF基序前后的酸性氨基酸残基静电相互作用。在与上述相似的条件下，苯佐卡因与叔胺型局部胺一样位于极头基团区域，但不能与III-IV连接体相互作用。IMF基元周围的结构一般为α-螺旋结构。IMF基序周围的结构是由IMF中异亮氨酸和苏氨酸之间的氢键控制的，苏氨酸位于IMF残基之后。五肽KIFMK与III-IV连接体特异性相互作用，稳定了IMF基序结构周围的α-螺旋结构。作为治疗苏氨酸突变为蛋氨酸的先天性副肌张力症（PMC）的药物，认为一种能够稳定野生型钠中IFMT基序形成的α-螺旋结构的分子可能是一种很好的药物。

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.