title: Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8.
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.
authors.affiliation: 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.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Maher
authors.affiliation: 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.).
authors.forename: Nyantsz
authors.initials: N
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Suchitra
authors.initials: S
authors.lastname: Ravula
authors.affiliation: 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.).
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ameriks
authors.affiliation: 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.).
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.affiliation: 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.).
authors.forename: Changlu
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: 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.).
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Wyatt
authors.affiliation: 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.).
authors.forename: Jose A
authors.initials: JA
authors.lastname: Matta
authors.affiliation: 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.).
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.affiliation: 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.).
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
authors.affiliation: 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.).
authors.forename: Luc
authors.initials: L
authors.lastname: Ver Donck
authors.affiliation: 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.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: 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.).
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.affiliation: 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.).
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.affiliation: 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.).
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects; D015195:Drug Design; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000235:genetics
chemical_list: C000609784:5-(2-chloro-6-(trifluoromethoxy)phenyl)-1,3-dihydrobenzimidazol-2-one; D001562:Benzimidazoles; C521178:CACNG8 protein, human; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA