title: Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators.
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.
authors.affiliation: 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.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: 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.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Reed
authors.affiliation: 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.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: 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.
authors.forename: Thanos
authors.initials: T
authors.lastname: Tzounopoulos
mesh_terms: D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D017124:Conserved Sequence; D006224:Cricetinae; D003412:Cricetulus; D004357:Drug Synergism; D054879:Halogenation; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism
chemical_list: D002219:Carbamates; D051656:KCNQ Potassium Channels; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; D021122:Protein Subunits; C101866:ezogabine; D014364:Tryptophan