TY - JOUR T1 - Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators JF - Molecular Pharmacology JO - Mol Pharmacol SP - 667 LP - 677 DO - 10.1124/mol.115.103200 VL - 89 IS - 6 AU - Manoj Kumar AU - Nicholas Reed AU - Ruiting Liu AU - Elias Aizenman AU - Peter Wipf AU - Thanos Tzounopoulos Y1 - 2016/06/01 UR - http://molpharm.aspetjournals.org/content/89/6/667.abstract N2 - KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating 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 anticonvulsant approved by the U.S. Food and Drug Administration. 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 Ethyl (2-amino-3-fluoro-4-((4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (RL648_81), a new KCNQ2/3-specific activator that is >15 times more potent and also more selective than retigabine. We suggest that RL648_81 is a promising clinical candidate for treating or preventing neurologic disorders associated with neuronal hyperexcitability. ER -