Chimeric derivatives of functionalized amino acids and α-aminoamides: Compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels

Robert Torregrosa, Xiao Fang Yang, Erik T. Dustrude, Theodore R. Cummins, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4′-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4′-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI = TD<inf>50</inf>/ED<inf>50</inf>) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNa<inf>V</inf>1.1, rNa<inf>V</inf>1.3, hNa<inf>V</inf>1.5, or hNa<inf>V</inf>1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

Original languageEnglish (US)
Pages (from-to)3655-3666
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number13
DOIs
StatePublished - Jan 1 2015

Keywords

  • a-Aminoamides
  • Antiseizure agents
  • Chimeric agents
  • Functionalized amino acids
  • Na+ current inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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