Abstract

KCNQ channels are voltage-gated, non-inactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an FDA approved anti-convulsant. By introducing a CF₃ - group at the 4-position of the benzylamine moiety, combined with a fluorine atom at the 3-position of the aniline ring, we generated RL648_81, a new KCNQ2/3-specific activator (EC₅₀ 190 nM) that is >15 times more potent and also more selective than retigabine (EC₅₀ 3.3 μM). We suggest that RL648_81 is a promising clinical candidate for treating or preventing neurological disorders associated with neuronal hyperexcitability.