Targeted blockade of TARP-γ8-associated AMPA receptors: Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611)

Jeffrey M. Witkin, Douglas A. Schober, Scott D. Gleason, John T. Catlow, Warren J. Porter, Jon Reel, Xiaoming Jin, Jonathan Hobbs, Donald Gehlert, Douglas L. Gernert, Kevin M. Gardinier, Akihiko S. Kato, Xingjie Ping, Jodi Smith

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background & Objective: 6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient. Results & Conclusion: Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.

Original languageEnglish (US)
Pages (from-to)1099-1110
Number of pages12
JournalCNS and Neurological Disorders - Drug Targets
Volume16
Issue number10
DOIs
StatePublished - Dec 1 2017

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AMPA Receptors
Anticonvulsants
Seizures
Proteins
Absence Epilepsy
Pentylenetetrazole
Genetic Models
Amygdala
Epilepsy
Hippocampus
Brain

Keywords

  • AMPA receptors
  • Antagonist
  • Anticonvulsant activity
  • CERC-611
  • LY3130481
  • TARP-g8
  • Transmembrane

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pharmacology

Cite this

Targeted blockade of TARP-γ8-associated AMPA receptors : Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611). / Witkin, Jeffrey M.; Schober, Douglas A.; Gleason, Scott D.; Catlow, John T.; Porter, Warren J.; Reel, Jon; Jin, Xiaoming; Hobbs, Jonathan; Gehlert, Donald; Gernert, Douglas L.; Gardinier, Kevin M.; Kato, Akihiko S.; Ping, Xingjie; Smith, Jodi.

In: CNS and Neurological Disorders - Drug Targets, Vol. 16, No. 10, 01.12.2017, p. 1099-1110.

Research output: Contribution to journalArticle

Witkin, JM, Schober, DA, Gleason, SD, Catlow, JT, Porter, WJ, Reel, J, Jin, X, Hobbs, J, Gehlert, D, Gernert, DL, Gardinier, KM, Kato, AS, Ping, X & Smith, J 2017, 'Targeted blockade of TARP-γ8-associated AMPA receptors: Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611)', CNS and Neurological Disorders - Drug Targets, vol. 16, no. 10, pp. 1099-1110. https://doi.org/10.2174/1871527316666171101132047
Witkin, Jeffrey M. ; Schober, Douglas A. ; Gleason, Scott D. ; Catlow, John T. ; Porter, Warren J. ; Reel, Jon ; Jin, Xiaoming ; Hobbs, Jonathan ; Gehlert, Donald ; Gernert, Douglas L. ; Gardinier, Kevin M. ; Kato, Akihiko S. ; Ping, Xingjie ; Smith, Jodi. / Targeted blockade of TARP-γ8-associated AMPA receptors : Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611). In: CNS and Neurological Disorders - Drug Targets. 2017 ; Vol. 16, No. 10. pp. 1099-1110.
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AU - Schober, Douglas A.

AU - Gleason, Scott D.

AU - Catlow, John T.

AU - Porter, Warren J.

AU - Reel, Jon

AU - Jin, Xiaoming

AU - Hobbs, Jonathan

AU - Gehlert, Donald

AU - Gernert, Douglas L.

AU - Gardinier, Kevin M.

AU - Kato, Akihiko S.

AU - Ping, Xingjie

AU - Smith, Jodi

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