1. Academic Validation
  2. Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8

  • J Pharmacol Exp Ther. 2016 May;357(2):394-414. doi: 10.1124/jpet.115.231712.
Michael P Maher 1 Nyantsz Wu 2 Suchitra Ravula 2 Michael K Ameriks 2 Brad M Savall 2 Changlu Liu 2 Brian Lord 2 Ryan M Wyatt 2 Jose A Matta 2 Christine Dugovic 2 Sujin Yun 2 Luc Ver Donck 2 Thomas Steckler 2 Alan D Wickenden 2 Nicholas I Carruthers 2 Timothy W Lovenberg 2
Affiliations

Affiliations

  • 1 Janssen Research and Development, LLC, Neuroscience Therapeutic Area, San Diego, California (M.P.M., N.W., S.R., M.K.A., B.M.S., C.L., B.L., R.M.W., J.A.M., C.D., S.Y., A.D.W., N.I.C., T.W.L.); and Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Neuroscience Therapeutic Area, Beerse, Belgium (L.V.D., T.S.) mmaher1@its.jnj.com.
  • 2 Janssen Research and Development, LLC, Neuroscience Therapeutic Area, San Diego, California (M.P.M., N.W., S.R., M.K.A., B.M.S., C.L., B.L., R.M.W., J.A.M., C.D., S.Y., A.D.W., N.I.C., T.W.L.); and Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Neuroscience Therapeutic Area, Beerse, Belgium (L.V.D., T.S.).
Abstract

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.

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