ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 105 citations in OpenAlex.
- Article
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- Inhibition of Cortical Evoked Responses to Sound Pulses by Preceding Silent Gaps.Journal of the Association for Research in Otolaryngology : JARO · 2025Article
- Involvement of BK Channels and Ryanodine Receptors in Salicylate-induced Tinnitus.Molecular neurobiology · 2025Article
- Targeting Kv7 Potassium Channels for Epilepsy.CNS drugs · 2025Review
- Unravelling the Silence: Exploring Tinnitus Pathophysiology and the Promise of Traditional Chinese Medicine.International journal of general medicine · 2025Review
- The involvement of KTranslational psychiatry · 2024Review
- In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review.Molecules (Basel, Switzerland) · 2024Review
- KCNT1 Channel Blockers: A Medicinal Chemistry Perspective.Molecules (Basel, Switzerland) · 2024Review
- Potassium channel-related epilepsy: Pathogenesis and clinical features.Epilepsia open · 2024Review
- Selective KCNQ2/3 Potassium Channel Opener ICA-069673 Inhibits Excitability in Mouse Vagal Sensory Neurons.The Journal of pharmacology and experimental therapeutics · 2024Article
- Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.The Journal of clinical investigation · 2023Article
- Acute Treatment with the M-Channel (KNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Site and Mechanism of ML252 Inhibition of Kv7 Voltage-Gated Potassium Channels.Function (Oxford, England) · 2023Article
- Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity.Journal of medicinal chemistry · 2022Article
- KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.JCI insight · 2022Article
- What's the buzz? The neuroscience and the treatment of tinnitus.Physiological reviews · 2021Review
- The KNeuroscience · 2021Article
- Chemical modulation of Kv7 potassium channels.RSC medicinal chemistry · 2021Review
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
Voltage-gated Kv7 (KCNQ) channels are voltage-dependent potassium channels that are activated at resting membrane potentials and therefore provide a powerful brake on neuronal excitability. Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus. Retigabine, a small molecule that activates KCNQ2-5 channels by shifting their voltage-dependent opening to more negative voltages, is an US Food and Drug Administration (FDA) approved anti-epileptic drug. However, recently identified side effects have limited its clinical use. As a result, the development of improved KCNQ2/3 channel activators is crucial for the treatment of hyperexcitability-related disorders. By incorporating a fluorine substituent in the 3-position of the tri-aminophenyl ring of retigabine, we synthesized a small-molecule activator (SF0034) with novel properties. Heterologous expression of KCNQ2/3 channels in HEK293T cells showed that SF0034 was five times more potent than retigabine at shifting the voltage dependence of KCNQ2/3 channels to more negative voltages. Moreover, unlike retigabine, SF0034 did not shift the voltage dependence of either KCNQ4 or KCNQ5 homomeric channels. Conditional deletion of Kcnq2 from cerebral cortical pyramidal neurons showed that SF0034 requires the expression of KCNQ2/3 channels for reducing the excitability of CA1 hippocampal neurons. Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus.
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