title: Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator.
abstract: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application.
  
  
  
  [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent.
  
  
  
  We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg-1. UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg-1.
  
  
  
  We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.
authors.affiliation: University of Sussex, Brighton, UK.|Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Ward
authors.affiliation: University of Sussex, Brighton, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Beswick
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
authors.forename: Novella
authors.initials: N
authors.lastname: Calcinaghi
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gartlon
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziani
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.|Health Sciences Research Center, Whiteland's College, University of Roehampton, London, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Selina Mok
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Pardoe
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Starr
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Woolley
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Harries
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006801:Humans; D007192:Indenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D007192:Indenes; C551959:N-(5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide; D018697:Nootropic Agents; D018091:Receptors, AMPA; D013449:Sulfonamides; D012601:Scopolamine