title: Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro.
abstract: The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.
authors.affiliation: NPS Allelix Corporation, 6850 Goreway Drive, Mississauga, Ontario L4V 1V7, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Miu
authors.forename: K R
authors.initials: KR
authors.lastname: Jarvie
authors.forename: V
authors.initials: V
authors.lastname: Radhakrishnan
authors.forename: M R
authors.initials: MR
authors.lastname: Gates
authors.forename: A
authors.initials: A
authors.lastname: Ogden
authors.forename: P L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: H
authors.initials: H
authors.lastname: Zarrinmayeh
authors.forename: K
authors.initials: K
authors.lastname: Ho
authors.forename: D
authors.initials: D
authors.lastname: Peters
authors.forename: J
authors.initials: J
authors.lastname: Grabell
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: D M
authors.initials: DM
authors.lastname: Zimmerman
authors.forename: D
authors.initials: D
authors.lastname: Bleakman
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D000959:Antihypertensive Agents; D001581:Benzothiadiazines; D004149:Dioxoles; D018690:Excitatory Amino Acid Agonists; C434043:LY 392098; C430915:LY 404187; D010880:Piperidines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D011994:Recombinant Proteins; D013449:Sulfonamides; D013876:Thiophenes; C004639:cyclothiazide; D002118:Calcium