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: Ki Duk Park, Xiao-Fang Yang, Erik T Dustrude, Yuying Wang, Matthew S Ripsch, Fletcher A White, Rajesh Khanna, Harold Kohn
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 2 Pg. 316-30 (Feb 18 2015) ISSN: 1948-7193 [Electronic] United States
• PMID: 25418676 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Analgesics
• Anticonvulsants
• Benzylamines
• Voltage-Gated Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• Formaldehyde
• Lacosamide
• safinamide
• Alanine

Topics

• Acetamides (chemistry, pharmacology)
• Alanine (analogs & derivatives, chemistry, pharmacology)
• Analgesics (chemistry, pharmacology)
• Animals
• Anticonvulsants (chemistry, pharmacology)
• Benzylamines (chemistry, pharmacology)
• Cells, Cultured
• Cerebral Cortex (drug effects, physiology)
• Disease Models, Animal
• Female
• Formaldehyde
• Lacosamide
• Male
• Membrane Potentials (drug effects)
• Mice
• Neuralgia (drug therapy, etiology)
• Neurons (drug effects, physiology)
• Patch-Clamp Techniques
• Rats, Sprague-Dawley
• Seizures (drug therapy)
• Tibial Nerve (injuries)
• Voltage-Gated Sodium Channel Blockers (chemistry, pharmacology)
• Voltage-Gated Sodium Channels (metabolism)