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

1.在生理条件下具有电荷的叔胺型局部麻醉剂与III-IV接头的疏水基序IMF中的苯丙氨酸残基疏水相互作用，并且还与位于IMF基序之前和之后的酸性氨基酸残基静电相互作用。在与上述类似的条件下，苯并咪唑与叔胺型局部麻醉剂一样位于极性头基团区域，但不能与III-IV连接体相互作用。IMF基序周围的结构一般为α-螺旋。IMF基序周围的结构由IMF中的异亮氨酸和位于IMF残基之后的苏氨酸之间的氢键控制。五肽KIFMK与III-IV接头特异性相互作用，并稳定IMF基序结构周围的α-螺旋结构。作为其中苏氨酸突变为甲硫氨酸的先天性副肌强直（PMC）的治疗剂，认为可以稳定野生型钠中IFMT基序形成的α-螺旋结构的分子可以是良好的药物。

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.