1. 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.
- Author
-
Torregrosa R, Yang XF, Dustrude ET, Cummins TR, Khanna R, and Kohn H
- Subjects
- Acetamides pharmacology, Administration, Oral, Amides pharmacology, Amino Acids pharmacology, Animals, Anticonvulsants pharmacology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cerebral Cortex pathology, Electroshock, HEK293 Cells, Humans, Injections, Intraperitoneal, Male, Mice, Neurons drug effects, Neurons metabolism, Neurons pathology, Patch-Clamp Techniques, Primary Cell Culture, Rats, Rats, Sprague-Dawley, Seizures metabolism, Seizures pathology, Structure-Activity Relationship, Voltage-Gated Sodium Channel Blockers pharmacology, Acetamides chemical synthesis, Amides chemical synthesis, Amino Acids chemical synthesis, Anticonvulsants chemical synthesis, Seizures prevention & control, Voltage-Gated Sodium Channel Blockers chemical synthesis, Voltage-Gated Sodium Channels metabolism
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF