Arizona Health Sciences

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.

TitleChimeric 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.
Publication TypeJournal Article
Year of Publication2015
AuthorsTorregrosa R, Yang X-F, Dustrude ET, Cummins TR, Khanna R, Kohn H
JournalBioorg Med Chem
Volume23
Issue13
Pagination3655-66
Date Published2015 Jul 1
ISSN1464-3391
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.

DOI10.1016/j.bmc.2015.04.014
Alternate JournalBioorg. Med. Chem.
PubMed ID25922183
PubMed Central IDPMC4461516
Grant List1 R41 NS080278 / NS / NINDS NIH HHS / United States
HHSN-271-2008-00025-C / / PHS HHS / United States
NS053422 / NS / NINDS NIH HHS / United States
R01 NS053422 / NS / NINDS NIH HHS / United States
R41 NS080278 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Rajesh Khanna, Ph.D.