Discovery and Evaluation of E0714 as an Antiepileptic Candidate: A Highly Subtype-Selective Kv7 Agonist within the Kv7 Family Designed Based on a Kv7.2-Specific Pocket

Subtype
selectivity is critical in drug development,
since off-target
effects can restrict clinical application. Kv7.2 is a key target for
treating neuronal hyperexcitability disorders. Nonselective activation
of Kv7 channels can cause multisystem effects and increase therapeutic
risk. Through a detailed analysis of Kv7 subtypes, we identified Kv7.2-specific
residues to design a selective binding pocket. E0714 was then developed
based on this pocket by virtual screening and compound modification.
Electrophysiology assays demonstrated that E0714 potently activates
Kv7.2 without significantly affecting Kv7.1, Kv7.3, Kv7.4, or Kv7.5.
E0714 exhibited an excellent antiepileptic effect in classical epilepsy
models without causing motor coordination problems. Mechanistic studies
revealed that E0714 targets the Kv7.2-specific residues F112, Y118,
and N289, which are responsible for the compound’s subtype-selective
activation. These findings clarify the mechanism of action of E0714
and provide a framework for designing highly selective drugs against
other Kv7 subtypes.