TY - JOUR
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 R.
AU - Khanna, Rajesh
AU - Kohn, Harold
N1 - Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015
Y1 - 2015
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.
KW - Antiseizure agents
KW - Chimeric agents
KW - Functionalized amino acids
KW - Na+ current inhibition
KW - a-Aminoamides
UR - http://www.scopus.com/inward/record.url?scp=84937122009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937122009&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2015.04.014
DO - 10.1016/j.bmc.2015.04.014
M3 - Article
C2 - 25922183
AN - SCOPUS:84937122009
SN - 0968-0896
VL - 23
SP - 3655
EP - 3666
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 13
ER -