BackgroundThe α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates the majority of fast synaptic transmission within the mammalian brain. The ubiquitous expression of the primary subunits of AMPA receptors (AMPARs), and the lack of pharmacological selectivity amongst them, preclude regional or neuronal subtype specificity. In vivo, AMPARs comprise a variety of accessory proteins. Of particular interest, TARP‐γ8 is highly expressed in the hippocampus, a region of the brain implicated in several psychiatric and neurological disorders.MethodsWe used high‐throughput screening to discover compounds that selectively modulate AMPARs containing TARP‐γ8. Subsequent medicinal chemistry efforts were used to improve potency and pharmacokinetics of the hits. Assays were developed to measure target occupancy and functional effects of the compounds in vivo.ResultsThese compounds possess a novel mechanism‐of‐action consistent with a partial attenuation of the interaction between the TARP and the pore‐forming subunits of the channel. Lead molecules with oral bioavailability and high brain penetration allowed demonstration of a strong relationship between pharmacokinetics and pharmacodynamics. The compounds show anticonvulsant and anxiolytic profiles in rodent. Molecules in this class provide large safety margins in preclinical species relative to non‐specific AMPAR antagonists due to the improved regional specificity of TARP‐γ8 modulators.ConclusionsAMPAR modulators selective for TARP‐γ8 have the potential to be novel treatments for anxiety/depression, bipolar disorder, temporal lobe epilepsy, and/or prodromal schizophrenia. This project also represents proof‐of‐concept for pharmacological targeting of accessory proteins and small‐molecule modulation of protein‐protein interactions.Support or Funding InformationAuthors are employees of Janssen R & D, LLCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.