ezogabine (XEN496) / Xenon - LARVOL DELTA

Voltage-sensor conformational microenvironments encode isoform-selective ion channel activation. (PubMed, Proc Natl Acad Sci U S A) - "Unexpectedly, CA potentiates Kv7.2/3 activation by retigabine via ligand-initiated positive allosteric coupling between the VSD and pore, thus enhancing the anticonvulsant action of retigabine despite CA lacking standalone anticonvulsant activity. The findings establish a mechanistic framework in which isoform selectivity arises from VSD conformational microenvironments rather than canonical binding determinants and highlight the voltage sensor as a tunable target for developing selective Kv channel openers."

Journal

Kv7 channels as pharmacological targets for central nervous system diseases. (PubMed, Pharmacol Rev) - "Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products, and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges...SIGNIFICANCE STATEMENT: Kv7 channels are central regulators of neuronal excitability and are increasingly recognized as key therapeutic targets in multiple central nervous system disorders. Advancing our understanding of their pathophysiological role may enable the development of more selective and effective treatments for diseases driven by maladaptive changes in neuronal excitability."

Journal • Review • Alzheimer's Disease • CNS Disorders • Epilepsy • Mental Retardation • Movement Disorders • Musculoskeletal Pain • Pain • Parkinson's Disease • Psychiatry

KV7 channel activation inhibits human and murine myometrium contractility and delays delivery in a mouse model of preterm birth. (PubMed, Commun Med (Lond)) - "These findings support KV7 activation as a promising approach to suppress uterine contractility and hence delay preterm birth, highlighting a potential new direction for either drug repurposing or therapeutic development."

Journal • Preclinical

Molecular Basis for Activation to Inhibition Switching in Kv7.2 Channel Modulators. (PubMed, Angew Chem Int Ed Engl) - "In the present work, we describe the cryo-electron microscopy structures of human Kv7.2 channels in complex with two retigabine analogues: compound 60 (c60), which we previously described as a Kv7 activator with improved pharmacokinetic and pharmacodynamic properties, and the newly designed compound 106 (c106), which acts as a potent Kv7 blocker. Although both compounds occupy the same pocket at the S5-S6 interface in the pore domain, docking and molecular dynamics simulations and electrophysiological experiments revealed that the opposite functional behavior is due to their differential interaction, involving the L307 residue. Thus, we herein provide novel mechanistic insights into the molecular mechanisms governing Kv7 channel modulation by exogenous ligands which may prove useful to target Kv7 channels with more potent and selective modulators."

Journal • CNS Disorders • Depression • Epilepsy • Mental Retardation • Psychiatry

Peripheral sensory terminal degeneration is linked to sensory fiber hyperexcitability in paclitaxel-induced peripheral neuropathy. (PubMed, bioRxiv) - "Paclitaxel induces distal degeneration of intraepidermal sensory terminals, increases spontaneous discharge, and lowers the mechanical activation threshold of C-fibers, demonstrating that structural degeneration and functional abnormalities occur concurrently in the peripheral terminal. Retigabine prevents both structural and functional alterations, supporting peripheral sensory terminals as a therapeutic target for preventing chemotherapy-induced neuropathy."

Journal • Pain

Retigabine alleviates cognitive deficits, decreases neuropathology and activates the AKT/GSK-3β pathway in APP/PS1 transgenic mice. (PubMed, Behav Brain Res) - "Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ1-40 and Aβ1-42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • BACE1 • DLG4 • SYP

Antiseizure Medications Impact Mitochondrial Ion Channels via Novel Bioenergetic and Neural Mechanisms. (PubMed, J Integr Neurosci) - "Phenytoin and carbamazepine reduce voltage-dependent anion channel isoform 1 (VDAC1)-associated mitochondrial permeability by modulating the Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 protein (Bcl-2) ratio; ethosuximide limits mitochondrial Ca2+ overload through modulation of the MCU complex; valproic acid stabilizes NCLX function and prevents mPTP opening via antioxidant mechanisms; levetiracetam contributes to preserving intracellular Ca2+ handling; and mitoKATP activators, including diazoxide and retigabine, promote mitochondrial membrane potential stability and reduce seizure-induced reactive oxygen species (ROS) generation. The mitochondrial effects vary according to epilepsy subtype, contributing to the attenuation of hippocampal apoptosis in temporal lobe epilepsy and thalamocortical network modulation in generalized epilepsies. In this narrative review we examine the experimental and molecular evidence demonstrating how ASMs modulate mitochondrial ion..."

Journal • Review • B Cell Lymphoma • CNS Disorders • Epilepsy • Lymphoma • Oncology • BAX • VDAC1

From Retigabine to Azetukalner: Reviving Voltage-Gated Potassium Channels for Epilepsy Therapy. (PubMed, Arch Pharm (Weinheim)) - "This structural analog of retigabine exhibits improved metabolic stability, increased potency, and enhanced blood-brain barrier penetration compared with its predecessor. This review details the synthesis, physicochemical properties, and clinical results of azetukalner."

Journal • Review • CNS Disorders • Epilepsy • Pain

Circadian dysregulation of voltage-gated ion channels orchestrates cross-organ electrophysiological remodeling and therapeutic timing. (PubMed, Biochem Biophys Res Commun) - "Validation against published datasets via reanalysis in synchronized cell systems (MCF-10A → MDA-MB-231, U2OS, OCI-AML3) showed that NaV blockers (tetrodotoxin, lidocaine) or K+ openers (retigabine) restored rhythmicity, reduced ROS by ∼40%, and lowered proliferation by ∼35%. This integrative circadian-electrophysiological framework highlights tissue-specific trends in VGIC remodeling and suggests potential circadian-informed therapeutic strategies. While phase-dependent effects are supported in neuronal, retinal, and cardiac models, predictions for other organs remain inferred from transcriptomic data and require further experimental validation."

Journal • Cardiovascular • CNS Disorders • Epilepsy • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Ophthalmology • ARNTL • BMAL1 • BRCA • KCNH2 • KCNQ1OT1

Adaptive Enhancement of Voltage-Gated Potassium (Kv7) Channel Function Regulates Aortic Vascular Tone in Early Type 2 Diabetes (ENDO 2026) - "Endothelium-dependent and -independent vasorelaxation to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in phenylephrine (PE)-precontracted aortic rings using a Radnoti organ bath system...Kv7 channel function was assessed using retigabine, a Kv7 activator, and PE-induced vasoconstriction was measured before and after pretreatment with L-NAME or XE991, a Kv7 inhibitor...Together, these findings suggest adaptive regulation of aortic vascular tone in the early stage of diabetes, characterized by enhanced Kv7 channel influence and altered integration with NO signaling. Further studies are needed to define the mechanisms by which Kv7 channels modulate vascular reactivity in this model."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Discovery of fluoxakalner, a novel and preferential Kv7.2/7.3 channel opener for antinociception in mice. (PubMed, Bioorg Chem) - "However, retigabine (RTG), the first-in-class Kv7 opener, was withdrawn from clinical use due to its oxidative metabolites that cause tissue discoloration and toxicity...In contrast, metabolism in rat liver assays revealed fluoxakalner avoids the formation of both ortho- and para-quinone diimine species linked to RTG toxicity. Taken together, these findings identify fluoxakalner as a novel Kv7.2/7.3 opener and a promising lead compound for further development of effective and safe antinociceptive agents."

Journal • Preclinical • CNS Disorders • Epilepsy • NAV1

Kv7.2 loss-of-function causes early hyperexcitability and network remodelling. (PubMed, Brain) - "KCNQ2-LOF variants induced a biphasic dysfunction at both single-cell and network levels, characterized by early Kv7-driven hyperexcitability accompanied by a clear reduction M-current density, which was rescued by acute Retigabine treatment...Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF variants disrupt human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options."

Journal • CNS Disorders • Epilepsy

KCNQ2 Channel as a Druggable Epilepsy Target: Advances in Pharmacological Modifiers. (PubMed, CNS Neurol Disord Drug Targets) - "Pharmacological modifiers of Kv7- mediated currents, such as retigabine, have demonstrated the restoration of impaired M-currents, but safety concerns limit their clinical application. Recent progress has led to the development of nextgeneration Kv7 activators, such as XEN1101, as well as other investigational compounds with improved potency, selectivity, and tolerability...Safety considerations, biomarkers of treatment responsiveness, and neurodevelopmental effects require careful evaluation. Nonetheless, the evolving pharmacological landscape highlights KCNQ2 channels as attractive and druggable targets in epilepsy, offering opportunities for mechanism-based therapies that could transform the management of this rare but devastating DEE."

Journal • CNS Disorders • Epilepsy

Human iPSC‑based translational and reverse translational research for neurodegenerative diseases: emphasis on ALS and key advances. (PubMed, Jpn J Radiol) - "Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Potassium channel agonists emerging as treatment options for focal epilepsy: are we breaking new ground? (PubMed, Expert Opin Emerg Drugs) - "This mini-review summarizes the clinical evolution of Kv7 modulation, from the first-generation prototype ezogabine to more selective second-generation candidates. We outline the scientific rationale for targeting the M-current, review emerging clinical data for agents such as azetukalner (XEN1101) and opakalim (BHV-7000), and highlight preclinical strategies including dual-mechanism modulators and drug repurposing...Second-generation agents provide encouraging mechanistic and clinical proof-of-concept, but long-term success will depend on clear advantages in patient-centered outcomes over established ASMs. Future value is likely to lie in precision-medicine strategies for KCNQ2/3-related encephalopathies and a carefully defined role in managing neuropsychiatric comorbidities."

Journal • Review • CNS Disorders • Epilepsy • Psychiatry

Therapeutic Efficacy and Seizure Control with KCNQ2/3 Activators in Partial-onset Epilepsy: A Dose-response Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - "Objective To compare the efficacy of different doses of KCNQ2/3 activators—retigabine (RTG) and XEN1101—against placebo in reducing partial-onset seizure frequency. Separately, XEN1101 25 mg showed better treatment phase responder rates (OR 6.80[3.15, 14.7]), achieving a SUCRA ranking of 79.7% over RTG 600 mg (52.5%) and placebo (7.5%). Conclusions RTG 1200 mg represents the most effective dose for reducing seizure frequency and achieving seizure freedom, emphasizing the importance of selecting an adequate dose to maximize Kv7.2/7.3 channel activation."

Retrospective data • CNS Disorders • Epilepsy

Safety Outcomes of KCNQ2/3 Activators in Partial-onset Epilepsy: A Meta-analysis of Randomized Trials (AAN 2026) - "Objective To analyze the safety outcomes of KCNQ2/3 activators Background KCNQ2/3 activators: retigabine(RTG) and azetukalner (XEN1101) are promising treatments for partial onset seizures targeting neuronal excitability to reduce seizure frequency. Hence, careful dose optimization and close patient monitoring are essential to reduce these events. In future, strategies like dose calculation tailored to patients' genetic and clinical profiles should be developed, resulting in achieving the benefits without increasing harmful effects."

Retrospective data • CNS Disorders • Epilepsy • Movement Disorders

Potassium Channelopathies and Precision Medicine Approaches in Epilepsy: A Systematic Review of Personalized Treatment Strategies. (PubMed, Curr Neuropharmacol) - "These studies collectively offer valuable insights into precision medicines for genetic epilepsy caused by pathogenic potassium variants. This review is essential because it informs clinical decision-making, including the selection of antiepileptic drugs, thereby supporting its integration into routine clinical care for this population. However, the low level of evidence and the heterogeneity of data from the included studies limit the review."

Journal • CNS Disorders • Epilepsy

Retigabine ameliorates CRS-induced depressive-like behaviors and cognitive impairment by inhibiting endoplasmic reticulum stress-mediated apoptosis. (PubMed, Brain Res Bull) - "Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Psychiatry • Vascular Neurology • HSPA5

Autism-Related Phenotypes in a Heterozygous Scn2aR854Q Mouse Model and Their Partial Rescue via a Potassium Channel Opener. (PubMed, Neuropharmacology) - "Notably, acute administration of retigabine, a potassium channel opener, rescues specific ASD-related phenotypes, possibly by restoring decreased firing through reduction of slow sodium inactivation. Comparative analysis with Scn2a knockout models, which show similar current reduction, highlights the unique severity of R854Q, suggesting a role of Igp in modulating neurobehavioral outcomes and informing potential therapeutic strategies."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Epilepsy • Genetic Disorders • NAV1

C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons. (PubMed, Neurobiol Dis) - "The increased membrane excitability can be restored by Nav channel inhibitor riluzole and Kv7 channel activator retigabine. Our results suggest a rescuable ion channel-mediated hyperexcitability induced by poly-PR expression in cortical neurons, providing a foundation for developing targeted therapies for C9orf72 ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Neuro- And Neurite-Protective Benefits of Proprietary Kv7.4-Activating Otoprotective Drug Candidates Through Mitochondrial Modulation (ARO 2026) - "Results : Untreated rat dissociated cortical neuron cultures (control, no glutamate injury) was compared to glutamate-injury (20 μM) alone, or in combination with pre/post-treatment with ACOU082 (10/30/100/300/1000 nM), retigabine (3/10 μM) and BDNF (50 ng/mL)... These results clearly demonstrate a neuroprotective potential of ACOU082 with reduced cytochrome C release from mitochondria after excitotoxic insult, in addition to the previously reported otoprotective benefits in different hearing loss models. In addition to a potential for CNS benefits with systemic treatment, this also suggests potential treatment benefits in hearing loss from Kv7.4 activators on SGNs and neurites in the cochlea."

Otorhinolaryngology • BDNF

Impaired adrenergic regulation of Kv channels underlies LC hyperactivity and early-onset sleep disruption in AD-like amyloidogenic mice. (PubMed, Alzheimers Dement) - "These findings identify LC hyperexcitability as a mechanistic driver of early sleep disruption in AD and implicate α2A receptors and Kv7 channels as promising therapeutic targets for early intervention."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Sleep Disorder

Efficacy of a K+ Channel Agonist, XEN1101, For Preserving Contractility in Mouse Models of Hypokalemic Periodic Paralysis. (PubMed, Muscle Nerve) - "The KV7 potassium channel agonist XEN1101 is effective as both a prophylactic agent and as abortive therapy for management of low-K+ induced weakness in murine models of HypoPP. XEN1101 is more potent than the first-generation Kv7 agonist, retigabine, in our murine models of HypoPP and is also better tolerated in patients. These improvements provide a rationale for future clinical trials of XEN1101 in HypoPP patients."

Journal • Preclinical • CAV1 • NAV1

Efficacy of Retigabine in Treating Weakness in a Mouse Model of Hypokalemic Periodic Paralysis. (PubMed, Muscle Nerve) - "Kv7 channel activation by retigabine preserved contractile force even during sustained depolarization from severe hypokalemia. These findings extend prior work and support development of K+ channel agonists as a therapeutic approach for HypoKPP."

Journal • Preclinical