Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus.

Summary

Kv7 (KCNQ) channels brake neuronal excitability at resting potential; losing their activity is linked to both epilepsy and tinnitus. Retigabine, an FDA-approved KCNQ2-5 activator, has clinical side effects that limit its use. By modifying retigabine's structure, the authors created SF0034, five times more potent and more selective for KCNQ2/3 (sparing KCNQ4/5) than retigabine. SF0034 required KCNQ2/3 expression to reduce neuronal excitability, was a more potent and less toxic anticonvulsant than retigabine in rodents, and, critically, prevented the development of tinnitus in mice.

Key findings

• SF0034 is five times more potent than retigabine at shifting KCNQ2/3 voltage-dependence, and more selective (spares KCNQ4/5).
• More potent and less toxic anticonvulsant than retigabine in rodent seizure models.
• Prevented the development of tinnitus in mice.
• Proposed as a clinical candidate for both epilepsy and tinnitus prevention.