Park, Ki Duk Yang, Xiao-Fang Dustrude, Erik T. Wang, Yuying Ripsch, Matthew S. White, Fletcher A. Khanna, Rajesh Kohn, Harold 2024-01-20T08:00:53Z 2024-01-20T08:00:53Z 2021-08-31 2015-02 1948-7193 https://pubs.kist.re.kr/handle/201004/125841 The functionalized amino acid, lacosamide ((R)-2), and the a-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. English AMER CHEMICAL SOC SLOW INACTIVATION FORMALIN TEST ANTICONVULSANT ACTIVITIES ION CHANNELS MODEL RAT PNU-151774E MECHANISM CURRENTS BINDING Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the alpha-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide Article 10.1021/cn5002182 1 ACS CHEMICAL NEUROSCIENCE, v.6, no.2, pp.316 - 330 ACS CHEMICAL NEUROSCIENCE 6 2 316 330 scie scopus 000349813700013 2-s2.0-84923241401 Biochemistry & Molecular Biology Chemistry, Medicinal Neurosciences Biochemistry & Molecular Biology Pharmacology & Pharmacy Neurosciences & Neurology Article SLOW INACTIVATION FORMALIN TEST ANTICONVULSANT ACTIVITIES ION CHANNELS MODEL RAT PNU-151774E MECHANISM CURRENTS BINDING antiseizure activity antinociception activity Chimeric compounds functionalized amino acids (lacosamide) alpha-aminoamides (safinamide) sodium channel activity