Glutamate mediates fast synaptic transmission in the central nervous system (CNS) via activation of ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Although AMPA receptors (AMPARs) are widely distributed throughout the CNS, their activity can be modulated by numerous auxiliary proteins, including transmembrane regulatory proteins (TARPs), which have more distinct expression profiles. For instance, TARP gamma-8 is highly enriched in the hippocampus as well as certain subregions of the forebrain, with minimal localization in the cerebellum. In rodents, selective negative modulation of AMPARs associated with TARP gamma-8 attenuates hyperexcitability in the hippocampus without direct effects on the midbrain or hind brain. Since excitatory neurotransmission is critical for the genesis and propagation of seizures, selective AMPAR/TARP gamma-8 negative modulators may function as effective anticonvulsants with an improved therapeutic index compared to current antiepileptic drugs, including the non-TARP selective AMPAR antagonist perampanel (Fycompa<sup>TM</sup>), which inhibit synaptic transmission throughout the CNS. Herein, we present the medicinal chemistry efforts that resulted in the identification of a novel TARP gamma-8 selective AMPAR negative modulator that has progressed to clinical trials. Aspects of lead optimization, candidate selection, and pharmacological mechanism of action will be highlighted as well.

Identification of a novel TARP gamma-8 selective AMPAR negative modulator for the treatment of epilepsy and related disorders

ACS Spring 2022

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