title: Identification and electrophysiological evaluation of 2-methylbenzamide derivatives as Nav1.1 modulators.
abstract: Voltage-gated sodium channels (Nav) are crucial to the initiation and propagation of action potentials (APs) in electrically excitable cells, and during the past decades they have received considerable attention due to their therapeutic potential. Here, we report for the first time the synthesis and the electrophysiological evaluation of 16 ligands based on a 2-methylbenzamide scaffold that have been identified as Nav1.1 modulators. Among these compounds, N,N'-(1,3-phenylene)bis(2-methylbenzamide) (3a) has been selected and evaluated in ex-vivo experiments in order to estimate the activation impact of such a compound profile. It appears that 3a increases the Nav1.1 channel activity although its overall impact remains moderate. Altogether, our preliminary results provide new insights into the development of small molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating CNS diseases.
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: François
authors.initials: F
authors.lastname: Crestey
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Kristen
authors.initials: K
authors.lastname: Frederiksen
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Jensen
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Dekermendjian
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Larsen
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: †ChemPartner Co. Ltd., 998 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Dunguo
authors.initials: D
authors.lastname: Lu
authors.affiliation: †ChemPartner Co. Ltd., 998 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Henry
authors.initials: H
authors.lastname: Liu
authors.affiliation: †ChemPartner Co. Ltd., 998 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yang
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: §Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Svenstrup
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000378:metabolism*; D051381:Rats; D046509:Tissue Culture Techniques
chemical_list: D001549:Benzamides; D049990:Membrane Transport Modulators; D062550:NAV1.1 Voltage-Gated Sodium Channel; C000607490:2-methylbenzamide
keywords: 2-Methylbenzamide derivatives; Nav1.1 modulator; brain slices; fast-spiking interneurons; voltage-gated sodium channels