A channel involved in pain perception: Voltage-gated sodium (Nav) channels propagate electrical signals in muscle cells and neurons. In humans, Nav1.7 plays a key role in pain perception. It is challenging to target a particular Nav isoform; however, arylsulfonamide antagonists selective for Nav1.7 have been reported recently. Ahuja et al. characterized the binding of these small molecules to human Nav channels. To further investigate the mechanism, they engineered a bacterial Nav channel to contain features of the Nav1.7 voltage-sensing domain that is targeted by the antagonist and determined the crystal structure of the chimera bound to an inhibitor. The structure gives insight into the mechanism of voltage sensing and will enable the design of more-selective Nav channel antagonists. Science , this issue p. 10.1126/science.aac5464

—Potassium channels encoded by HERG underlieI_Kr, a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such asdd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating indd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd²⁺, removal of extracellular Na⁺) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 μmol/Ldd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduceddd-sotalol block of HERG: 100 μmol/L Cd²⁺reduced steady-state block to 55% at +20 mV (P<0.05); removing extracellular Na⁺reduced block to 44% (P<0.05). An inactivation-disabling mutation (G628C-S631C) reduceddd-sotalol block to only 11% (P<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduceddd-sotalol block to 49% (P<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modifydd-sotalol block. We postulate thatdd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na_V1.6 channels. Such a molecule provides a precision-medicine approach to targetSCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess Na_V1.6 sodium current, or other indications where Na_V1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of Na_V1.6 (IC₅₀0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for Na_V1.1, 134 X for Na_V1.2, 276 X for Na_V1.7, and >583 Xfor Na_V1.3, Na_V1.4, and Na_V1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting Na_V1.6 currents, including resurgent and persistent Na_V1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where Na_V1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in aScn8aGoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment ofSCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.