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

Ki Duk Park, Xiao Fang Yang, Erik T. Dustrude, Yuying Wang, Matthew S. Ripsch, Fletcher A. White, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)316-330
Number of pages15
JournalACS Chemical Neuroscience
Volume6
Issue number2
DOIs
StatePublished - Feb 18 2015

Keywords

  • Chimeric compounds
  • antinociception activity
  • antiseizure activity
  • functionalized amino acids (lacosamide)
  • sodium channel activity
  • α-aminoamides (safinamide)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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