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Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents

John Gilchrist, Stacey Dutton, Marcelo Diaz-Bustamante, Annie McPherson, Nicolas Olivares, Jeet Kalia, Andrew Escayg and Frank Bosmans (UGent)
(2014) ACS CHEMICAL BIOLOGY. 9(5). p.1204-1212
Author
Organization
Abstract
Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Na-v) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Na(v)1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNa(v)1.1. Subsequent structure-activity relationship experiments with related N-benzyl triazole compounds on four brain hNa(v) channel isoforms revealed a novel drug variant that (1) shifts hNa(v)1.1 opening to more depolarized voltages without further alterations in the gating properties of hNa(v)1.1, hNa(v)1.2, hNa(v)1.3, and hNa(v)1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Na-v channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Na-v channel isoforms while limiting adverse effects.
Keywords
GATED SODIUM-CHANNEL, LENNOX-GASTAUT-SYNDROME, SEVERE MYOCLONIC EPILEPSY, ANTIEPILEPTIC DRUGS, HUMAN BRAIN, HEMIPLEGIC MIGRAINE, ANTICONVULSANT DRUG, FUNCTIONAL-ANALYSIS, MOUSE MODEL, RUFINAMIDE

Citation

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MLA
Gilchrist, John, et al. “Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents.” ACS CHEMICAL BIOLOGY, vol. 9, no. 5, 2014, pp. 1204–12, doi:10.1021/cb500108p.
APA
Gilchrist, J., Dutton, S., Diaz-Bustamante, M., McPherson, A., Olivares, N., Kalia, J., … Bosmans, F. (2014). Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS CHEMICAL BIOLOGY, 9(5), 1204–1212. https://doi.org/10.1021/cb500108p
Chicago author-date
Gilchrist, John, Stacey Dutton, Marcelo Diaz-Bustamante, Annie McPherson, Nicolas Olivares, Jeet Kalia, Andrew Escayg, and Frank Bosmans. 2014. “Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents.” ACS CHEMICAL BIOLOGY 9 (5): 1204–12. https://doi.org/10.1021/cb500108p.
Chicago author-date (all authors)
Gilchrist, John, Stacey Dutton, Marcelo Diaz-Bustamante, Annie McPherson, Nicolas Olivares, Jeet Kalia, Andrew Escayg, and Frank Bosmans. 2014. “Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents.” ACS CHEMICAL BIOLOGY 9 (5): 1204–1212. doi:10.1021/cb500108p.
Vancouver
1.
Gilchrist J, Dutton S, Diaz-Bustamante M, McPherson A, Olivares N, Kalia J, et al. Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS CHEMICAL BIOLOGY. 2014;9(5):1204–12.
IEEE
[1]
J. Gilchrist et al., “Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents,” ACS CHEMICAL BIOLOGY, vol. 9, no. 5, pp. 1204–1212, 2014.
@article{8584523,
  abstract     = {{Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Na-v) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Na(v)1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNa(v)1.1. Subsequent structure-activity relationship experiments with related N-benzyl triazole compounds on four brain hNa(v) channel isoforms revealed a novel drug variant that (1) shifts hNa(v)1.1 opening to more depolarized voltages without further alterations in the gating properties of hNa(v)1.1, hNa(v)1.2, hNa(v)1.3, and hNa(v)1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Na-v channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Na-v channel isoforms while limiting adverse effects.}},
  author       = {{Gilchrist, John and Dutton, Stacey and Diaz-Bustamante, Marcelo and McPherson, Annie and Olivares, Nicolas and Kalia, Jeet and Escayg, Andrew and Bosmans, Frank}},
  issn         = {{1554-8929}},
  journal      = {{ACS CHEMICAL BIOLOGY}},
  keywords     = {{GATED SODIUM-CHANNEL,LENNOX-GASTAUT-SYNDROME,SEVERE MYOCLONIC EPILEPSY,ANTIEPILEPTIC DRUGS,HUMAN BRAIN,HEMIPLEGIC MIGRAINE,ANTICONVULSANT DRUG,FUNCTIONAL-ANALYSIS,MOUSE MODEL,RUFINAMIDE}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{1204--1212}},
  title        = {{Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents}},
  url          = {{http://doi.org/10.1021/cb500108p}},
  volume       = {{9}},
  year         = {{2014}},
}
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