RT Journal Article
SR Electronic
T1 Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 667
OP 677
DO 10.1124/mol.115.103200
VO 89
IS 6
A1 Kumar, Manoj
A1 Reed, Nicholas
A1 Liu, Ruiting
A1 Aizenman, Elias
A1 Wipf, Peter
A1 Tzounopoulos, Thanos
YR 2016
UL http://molpharm.aspetjournals.org/content/89/6/667.abstract
AB 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.