Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist

ACS Chem Neurosci. 2017 Dec 20;8(12):2631-2647. doi: 10.1021/acschemneuro.7b00186. Epub 2017 Sep 5.


The forebrain specific AMPA receptor antagonist, LY3130481/CERC-611, which selectively antagonizes the AMPA receptors associated with TARP γ-8, an auxiliary subunit enriched in the forebrain, has potent antiepileptic activities without motor side effects. We designated the compounds with such activities as γ-8 TARP dependent AMPA receptor antagonists (γ-8 TDAAs). In this work, we further investigated the mechanisms of action using a radiolabeled γ-8 TDAA and ternary structural modeling with mutational validations to characterize the LY3130481 binding to γ-8. The radioligand binding to the cells heterologously expressing GluA1 and/or γ-8 revealed that γ-8 TDAAs binds to γ-8 alone without AMPA receptors. Homology modeling of γ-8, based on the crystal structures of a distant TARP homologue, murine claudin 19, in conjunction with knowledge of two γ-8 residues previously identified as critical for the LY3130481 TARP-dependent selectivity provided the basis for a binding mode prediction. This allowed further rational mutational studies for characterization of the structural determinants in TARP γ-8 for LY3130481 activities, both thermodynamically as well as kinetically.

Keywords: Structural modeling; TDAA; glutamate receptor; ionotropic; stargazer; stargazin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles / chemistry*
  • Binding Sites
  • Hippocampus / chemistry
  • Male
  • Mice
  • Models, Biological
  • Models, Chemical
  • Molecular Docking Simulation*
  • Neurons / chemistry*
  • Protein Binding
  • Protein Conformation
  • Pyrazoles / chemistry*
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / ultrastructure*
  • Structure-Activity Relationship


  • Benzothiazoles
  • LY3130481
  • Pyrazoles
  • Receptors, AMPA