title: The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2.
abstract: The optimisation of an HTS hit series (1) leading to the identification of structurally novel, selective, orally bioavailable mGluR2 positive modulators GSK1331258 and GSK1331268 is described. Structure-activity relationships, attenuation of dopaminergic activity, and potentiation of mGluR2 responses in rat hippocampal MPP-DG synapses are also reported.
authors.affiliation: GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, UK.
authors.forename: Pier L
authors.initials: PL
authors.lastname: D'Alessandro
authors.forename: Corrado
authors.initials: C
authors.lastname: Corti
authors.forename: Adelheid
authors.initials: A
authors.lastname: Roth
authors.forename: Annarosa
authors.initials: A
authors.lastname: Ugolini
authors.forename: Anna
authors.initials: A
authors.lastname: Sava
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
authors.forename: Federica
authors.initials: F
authors.lastname: Bianchi
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Garland
authors.forename: Ben
authors.initials: B
authors.lastname: Powney
authors.forename: Emma L
authors.initials: EL
authors.lastname: Koppe
authors.forename: Magalie
authors.initials: M
authors.lastname: Rocheville
authors.forename: Greg
authors.initials: G
authors.lastname: Osborne
authors.forename: Paloma
authors.initials: P
authors.lastname: Perez
authors.forename: Jesús
authors.initials: J
authors.lastname: de la Fuente
authors.forename: Maite
authors.initials: M
authors.lastname: De Los Frailes
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Clive
authors.initials: C
authors.lastname: Branch
authors.forename: David
authors.initials: D
authors.lastname: Nash
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D057166:High-Throughput Screening Assays; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D055366:Synaptic Potentials / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; C548721:GSK 1331258; C548722:GSK 1331268; D010879:Piperazines; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D004298:Dopamine