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Mol Pharmacol. 2016 Jun;89(6):667-77. doi: 10.1124/mol.115.103200. Epub 2016 Mar 22.

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators.

Author information

1
Department of Otolaryngology, School of Medicine (M.K., T.T.); Department of Chemistry (N.R., R.L., P.W.); Department of Neurobiology (E.A., T.T.); and Pittsburgh Institute for Neurodegenerative Diseases, School of Medicine (E.A.), University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Department of Otolaryngology, School of Medicine (M.K., T.T.); Department of Chemistry (N.R., R.L., P.W.); Department of Neurobiology (E.A., T.T.); and Pittsburgh Institute for Neurodegenerative Diseases, School of Medicine (E.A.), University of Pittsburgh, Pittsburgh, Pennsylvania thanos@pitt.edu pwipf@pitt.edu.

Abstract

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.

PMID:
27005699
DOI:
10.1124/mol.115.103200
[Indexed for MEDLINE]
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