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 Cummins, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

7 Citations (Scopus)

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

Fingerprint

Voltage-Gated Sodium Channels
Sodium Channels
Anticonvulsants
Protein Isoforms
Seizures
Derivatives
Amino Acids
Rats
Electrophysiology
Electroshock
HEK293 Cells
Clamping devices
Neurons
Animals
Animal Models
Pharmaceutical Preparations
lacosamide

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

Cite this

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title = "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",
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 = TD50/ED50) 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 hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.",
keywords = "a-Aminoamides, Antiseizure agents, Chimeric agents, Functionalized amino acids, Na+ current inhibition",
author = "Robert Torregrosa and Yang, {Xiao Fang} and Dustrude, {Erik T.} and Theodore Cummins and Rajesh Khanna and Harold Kohn",
year = "2015",
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T1 - Chimeric derivatives of functionalized amino acids and α-aminoamides

T2 - Compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels

AU - Torregrosa, Robert

AU - Yang, Xiao Fang

AU - Dustrude, Erik T.

AU - Cummins, Theodore

AU - Khanna, Rajesh

AU - Kohn, Harold

PY - 2015

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N2 - 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 = TD50/ED50) 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 hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

AB - 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 = TD50/ED50) 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 hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

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