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Voltage-gated sodium channels (Na V s) are targets for a number of acute poisons. Many of these agents act as allosteric modulators of channel activity and serve as powerful chemical tools for understanding channel function. Herein, we detail studies with batrachotoxin (BTX), a potent steroidal amine, and three ester derivatives prepared through de novo synthesis against recombinant Na V subtypes (rNa V 1.4 and hNa V 1.5). Two of these compounds, BTX-B and BTX- c Hx, are functionally equivalent to BTX, hyperpolarizing channel activation and blocking both fast and slow inactivation. BTX-yne-a C20-n-heptynoate ester-is a conspicuous outlier, eliminating fast but not slow inactivation. This property differentiates BTX-yne among other Na V modulators as a unique reagent that separates inactivation processes. These findings are supported by functional studies with bacterial Na V s (BacNa V s) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding Na V gating mechanisms and designing allosteric regulators of Na V activity., Competing Interests: Declaration of interests J.D. is a cofounder, executive board member, and holds equity shares in SiteOne Therapeutics, Inc., a start-up company interested in developing subtype-selective modulators of Na(V)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)