C11‐Substituted Saxitoxin Derivatives as Potent Inhibitors of Tetrodotoxin‐Resistant Sodium Channel Na _V 1.5

ABSTRACT

Voltage‐gated sodium channel Na _V 1.5 is the principal cardiac sodium channel and an important target for probing channel function and disease‐associated excitability. Although saxitoxin (STX) potently inhibits several tetrodotoxin‐sensitive sodium‐channel subtypes, Na _V 1.5 is tetrodotoxin resistant, limiting the utility for this isoform. Here we report the design, synthesis, and functional evaluation of C11‐functionalized STX derivatives as potent Na _V 1.5 inhibitors. Introduction of a β‐oriented tertiary alcohol and an aralkyl substituent at C11 markedly enhanced activity relative to the α‐epimer. Structure–activity relationship studies identified 11β‐OH‐(3‐fluorobenzyl) STX as the most active derivative, with IC ₅₀ values of 6.1 ± 0.5 nM (Na _V 1.2) and 7.8 ± 1.2 nM (Na _V 1.5) in whole‐cell patch‐clamp recordings, and a lower potency toward Na _V 1.7 (58 ± 13 nM); these represent 4.1‐, 74‐, and 1.6‐fold reductions in IC ₅₀ relative to decarbamoylsaxitoxin (dcSTX). Its Na _V 1.5‐inhibitory profile was distinct from dcSTX, comprising moderate resting‐state block, little stabilization of the inactivated state, and progressive use‐dependent inhibition during repetitive depolarization. Molecular docking of C11 diastereomers suggested that both compounds bind in the Na _V 1.5 outer pore, with C11 stereochemistry affecting the orientation and interactions of the hydroxybenzyl substituent. These findings demonstrate that C11 functionalization effectively converts the STX scaffold into potent inhibitors of TTX‐resistant Na _V 1.5.