Discovery of the First α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ‑8

Transmembrane
AMPA receptor regulatory proteins (TARPs) are a family
of scaffolding proteins that regulate AMPA receptor trafficking and
function. TARP γ-8 is one member of this family and is highly
expressed within the hippocampus relative to the cerebellum. A selective
TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative
approach to modulate AMPA receptors in specific brain regions to potentially
increase the therapeutic index relative to known non-TARP-dependent
AMPA antagonists. We describe here, for the first time, the discovery
of a noncompetitive AMPA receptor antagonist that is dependent on
the presence of TARP γ-8. Three major iteration cycles were
employed to improve upon potency, CYP1A2-dependent challenges, and
in vivo clearance. An optimized molecule, compound (−)-25 (LY3130481), was fully protective against pentylenetetrazole-induced
convulsions in rats without the motor impairment associated with non-TARP-dependent
AMPA receptor antagonists. Compound (−)-25 could
be utilized to provide proof of concept for antiepileptic efficacy
with reduced motor side effects in patients.