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.
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.
NeuroGate Therapeutics, Inc., 150 Fayetteville Street, Suite 2300, Raleigh, NC 27601, United States.
Robert
R
Torregrosa
Department of Pharmacology and Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ 85742, United States.
Xiao-Fang
XF
Yang
Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Erik T
ET
Dustrude
Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Theodore R
TR
Cummins
Department of Pharmacology and Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ 85742, United States.
Rajesh
R
Khanna
NeuroGate Therapeutics, Inc., 150 Fayetteville Street, Suite 2300, Raleigh, NC 27601, United States; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, United States.
Harold
H
Kohn
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004597:Electroshock; D057809:HEK293 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D000081:Acetamides; D000577:Amides; D000596:Amino Acids; D000927:Anticonvulsants; C000605296:N-4'-((3'-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels
Antiseizure agents; Chimeric agents; Functionalized amino acids; Na(+) current inhibition; α-Aminoamides