title: Chimeric agents derived from the functionalized amino acid, lacosamide, and the α-aminoamide, safinamide: evaluation of their inhibitory actions on voltage-gated sodium channels, and antiseizure and antinociception activities and comparison with lacosamide and safinamide.
abstract: The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7-(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7-(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7-(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy and ‡Department of Chemistry, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.forename: Erik T
authors.initials: ET
authors.lastname: Dustrude
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005557:Formaldehyde; D000078334:Lacosamide; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D013979:Tibial Nerve / Q000293:injuries; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D000081:Acetamides; D000700:Analgesics; D000927:Anticonvulsants; D001596:Benzylamines; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D005557:Formaldehyde; D000078334:Lacosamide; C092797:safinamide; D000409:Alanine
keywords: Chimeric compounds; antinociception activity; antiseizure activity; functionalized amino acids (lacosamide); sodium channel activity; α-aminoamides (safinamide)