Merging structural motifs of functionalized amino acids and α-aminoamides results in novel anticonvulsant compounds with significant effects on slow and fast inactivation of voltage-gated sodium channels and in the treatment of neuropathic pain

Yuying Wang, Sarah M. Wilson, Joel M. Brittain, Matthew S. Ripsch, Christophe Salomé, Ki Duk Park, Fletcher A. White, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

We recently reported that merging key structural pharmacophores of the anticonvulsant drugs lacosamide (a functionalized amino acid) with safinamide (an α-aminoamide) resulted in novel compounds with anticonvulsant activities superior to that of either drug alone. Here, we examined the effects of six such chimeric compounds on Na+-channel function in central nervous system catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that these compounds affected Na+ channel fast and slow inactivation processes. Detailed electrophysiological characterization of two of these chimeric compounds that contained either an oxymethylene ((R)-7) or a chemical bond ((R)-11) between the two aromatic rings showed comparable effects on slow inactivation, use-dependence of block, development of slow inactivation, and recovery of Na+ channels from inactivation. Both compounds were equally effective at inducing slow inactivation; (R)-7 shifted the fast inactivation curve in the hyperpolarizing direction greater than (R)-11, suggesting that in the presence of (R)-7 a larger fraction of the channels are in an inactivated state. None of the chimeric compounds affected veratridine- or KCl-induced glutamate release in neonatal cortical neurons. There was modest inhibition of KCl-induced calcium influx in cortical neurons. Finally, a single intraperitoneal administration of (R)-7, but not (R)-11, completely reversed mechanical hypersensitivity in a tibial-nerve injury model of neuropathic pain. The strong effects of (R)-7 on slow and fast inactivation of Na+ channels may contribute to its efficacy and provide a promising novel therapy for neuropathic pain, in addition to its antiepileptic potential.

Original languageEnglish (US)
Pages (from-to)317-332
Number of pages16
JournalACS Chemical Neuroscience
Volume2
Issue number6
DOIs
StatePublished - Jun 15 2011
Externally publishedYes

Keywords

  • Lacosamide
  • neuropathic pain
  • safinamide
  • slow/fast inactivation
  • sodium channel
  • state-dependent

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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