The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2.
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.
D'Alessandro
Pier L
PL
GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, UK.
Corti
Corrado
C
Roth
Adelheid
A
Ugolini
Annarosa
A
Sava
Anna
A
Montanari
Dino
D
Bianchi
Federica
F
Garland
Stephen L
SL
Powney
Ben
B
Koppe
Emma L
EL
Rocheville
Magalie
M
Osborne
Greg
G
Perez
Paloma
P
de la Fuente
Jesús
J
De Los Frailes
Maite
M
Smith
Paul W
PW
Branch
Clive
C
Nash
David
D
Watson
Stephen P
SP
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
D001562:Benzimidazoles; C548721:GSK 1331258; C548722:GSK 1331268; D010879:Piperazines; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D004298:Dopamine