Electro‐Mechanical Uncoupling of K V 7.1 Voltage Sensor and Pore by 1,4‐Benzodiazepines Is Modulated by Decoration of Position 1

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ABSTRACT The voltage‐gated potassium channel K V 7.1 (KCNQ1) is essential for cardiac repolarization. Loss‐of‐function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of K V 7.1 are therefore of therapeutic interest. Among them, the 1,4‐benzodiazepine derivative (R)‐L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure–activity relationships (SAR) of (R)‐L3, we synthesized and functionally characterized a series of novel 1,4‐benzodiazepine derivatives and examined their effects on K V 7.1 gating. Human K V 7.1 channels were heterologously expressed in Xenopus laevis oocytes. Two‐electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4‐Benzodiazepines modified at 1‐position reproduced the canonical effects of (R)‐L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de‐)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4‐benzodiazepine scaffold at 1‐position shift the interaction between pore binding and voltage sensor–pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)‐L3 analogues can differentially modulate K V 7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next‐generation K V 7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in K V 7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.

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