Title:Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611)
Volume: 16
Issue: 10
Author(s): 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 and Jodi L. Smith
Affiliation:
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana,United States
Keywords:
AMPA receptors, antagonist, anticonvulsant activity, CERC-611, LY3130481, TARP-g8, transmembrane.
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.
