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

Ki Duk Park, Xiao Fang Yang, Erik T. Dustrude, Yuying Wang, Matthew S. Ripsch, Fletcher A. White, Rajesh Khanna, Harold Kohn

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)316-330
Number of pages15
JournalACS Chemical Neuroscience
Volume6
Issue number2
DOIs
StatePublished - Feb 18 2015

Fingerprint

Voltage-Gated Sodium Channels
Sodium Channels
Amino Acids
Anticonvulsants
Rats
Tibial Nerve
Aptitude
Neuralgia
Merging
Formaldehyde
Neurons
Catecholamines
Hypersensitivity
Animals
Seizures
Animal Models
Chemical activation
Pain
Kinetics
Wounds and Injuries

Keywords

  • antinociception activity
  • antiseizure activity
  • Chimeric compounds
  • functionalized amino acids (lacosamide)
  • sodium channel activity
  • α-aminoamides (safinamide)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

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. / Park, Ki Duk; Yang, Xiao Fang; Dustrude, Erik T.; Wang, Yuying; Ripsch, Matthew S.; White, Fletcher A.; Khanna, Rajesh; Kohn, Harold.

In: ACS Chemical Neuroscience, Vol. 6, No. 2, 18.02.2015, p. 316-330.

Research output: Contribution to journalArticle

@article{2dbb1297354645f0a1f7f82db63cb60b,
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.",
keywords = "antinociception activity, antiseizure activity, Chimeric compounds, functionalized amino acids (lacosamide), sodium channel activity, α-aminoamides (safinamide)",
author = "Park, {Ki Duk} and Yang, {Xiao Fang} and Dustrude, {Erik T.} and Yuying Wang and Ripsch, {Matthew S.} and White, {Fletcher A.} and Rajesh Khanna and Harold Kohn",
year = "2015",
month = "2",
day = "18",
doi = "10.1021/cn5002182",
language = "English (US)",
volume = "6",
pages = "316--330",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Chimeric agents derived from the functionalized amino acid, lacosamide, and the α-aminoamide, safinamide

T2 - Evaluation of their inhibitory actions on voltage-gated sodium channels, and antiseizure and antinociception activities and comparison with lacosamide and safinamide

AU - Park, Ki Duk

AU - Yang, Xiao Fang

AU - Dustrude, Erik T.

AU - Wang, Yuying

AU - Ripsch, Matthew S.

AU - White, Fletcher A.

AU - Khanna, Rajesh

AU - Kohn, Harold

PY - 2015/2/18

Y1 - 2015/2/18

N2 - 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.

AB - 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.

KW - antinociception activity

KW - antiseizure activity

KW - Chimeric compounds

KW - functionalized amino acids (lacosamide)

KW - sodium channel activity

KW - α-aminoamides (safinamide)

UR - http://www.scopus.com/inward/record.url?scp=84923241401&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923241401&partnerID=8YFLogxK

U2 - 10.1021/cn5002182

DO - 10.1021/cn5002182

M3 - Article

C2 - 25418676

AN - SCOPUS:84923241401

VL - 6

SP - 316

EP - 330

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 2

ER -