TY - JOUR T1 - Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-<em>γ</em>8 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 394 LP - 414 DO - 10.1124/jpet.115.231712 VL - 357 IS - 2 AU - Michael P. Maher AU - Nyantsz Wu AU - Suchitra Ravula AU - Michael K. Ameriks AU - Brad M. Savall AU - Changlu Liu AU - Brian Lord AU - Ryan M. Wyatt AU - Jose A. Matta AU - Christine Dugovic AU - Sujin Yun AU - Luc Ver Donck AU - Thomas Steckler AU - Alan D. Wickenden AU - Nicholas I. Carruthers AU - Timothy W. Lovenberg Y1 - 2016/05/01 UR - http://jpet.aspetjournals.org/content/357/2/394.abstract N2 - Members of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein γ8 (TARP-γ8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-γ8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets. ER -