Site-Specific Antagonists to Tetrodotoxin and Saxitoxin

Abstract

Abstract : The objective of this project is to generate more knowledge about the specific chemical structure of the tetrodotoxin (TTX)/saxitoxin (STX) binding site on the protein molecule of the voltage-gated sodium channel of many excitable membranes. From such knowledge, site-specific antagonists to these toxins and/or other sodium-channel effectors can be developed rationally. Towards the objective of developing site-specific antagonists to tetrodotoxin and saxitoxin chemical synthesis of simpler guanidine compounds are underway simultaneously as electrophysiological studies on newer natural and synthetic analogues of TTX on intact membranes. Synthetically, significant progress has been made in producing monosubstituted guanidine, which can then be coupled to sugars to form amino-monosaccharides. There are some structural resemblance between these compounds and the guanidinium end of the TTX molecule. Their biological activity will be tested at some future date when those compounds are fully characterized. On STX analogs work has been rather slow for lack of voucher standard material. However, as an essential first step in all that work, an HPLC analyzer has been completed for quantitative analysis of small amounts of STX and other PSP toxins. Electrophysiologically, 8 related dihydropyrimidine compounds have been found to have very little effect on interfering with the propagation of compound action potential in frog sciatic nerve fibers. 6,11 isopropylidene TTX and epi TTX have been found to affect the sodium channel, but at significantly lower potency than TTX. (KT)