Synthetic studies on Subtype Selective Na-channel Inhibitors based upon Saxitoxins Synthesis

电压门控钠通道（NaVCh）是跨膜蛋白，其有助于控制膜兴奋性和动作电位沿沿着的传播。迄今为止，已鉴定出9种NaVCh亚型，并且亚型选择性小分子被认为是NaVCh相关疾病的良好候选者。在这种情况下，开发NaVCh亚型选择性配体与石房蛤毒素（STX），贝类毒素，STX的SAR研究的基础上进行了检查。本课题研究了STX的一般合成方法，并合成了多种STX衍生物。还开发了STX的骨架类似物FD-STX，其为稠合型环系统。在所合成的化合物中，FD-dcSTX表现出非常独特的抑制作用，即：例如，它会抑制Nav 1 5（河豚毒素耐药亚型）不可逆。

Voltage-gated sodium channels(NaVCh) are transmembrane proteins that contribute to the control of membrane excitability and the propagation of action potentials along axons. To date, nine kinds of subtyps for NaVCh were identified, and subtype selective small molecules are considered to be good candidate for NaVCh related disease. In this context, development of NaVCh-subtype selective ligand with saxitoxin(STX), a shellfish toxin, was examined based on the SAR studies of STX. In this project, general synthetic method for STX was developed, and varieties of STX derivatives were synthesized. Skeletal analog of STX that posses fused-type ring system, FD-STX, was also developed. Among the compounds synthesized, FD-dcSTX shows very unique inhibitory manner, i. e., it inhibits Nav1. 5(tetrodotoxin-resistant subtype) irreversibly.