Park, Ki DukYang, Xiao-FangDustrude, Erik T.Wang, YuyingRipsch, Matthew S.White, Fletcher A.Khanna, RajeshKohn, Harold2016-10-192016-10-192015-02-18Park, K. D., Yang, X.-F., Dustrude, E. T., Wang, Y., Ripsch, M. S., White, F. A., … Kohn, H. (2015). Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the α-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide. ACS Chemical Neuroscience, 6(2), 316–330. http://doi.org/10.1021/cn50021821948-7193https://hdl.handle.net/1805/11188The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7-(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7-(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7-(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats.en-USIUPUI Open Access PolicyAcetamidespharmacologyAlanineanalogs & derivativesAnalgesicsAnticonvulsantsBenzylaminesVoltage-Gated Sodium Channel BlockersArticle