The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2

Pier L D'Alessandro; Corrado Corti; Adelheid Roth; Annarosa Ugolini; Anna Sava; Dino Montanari; Federica Bianchi; Stephen L Garland; Ben Powney; Emma L Koppe; Magalie Rocheville; Greg Osborne; Paloma Perez; Jesús de la Fuente; Maite De Los Frailes; Paul W Smith; Clive Branch; David Nash; Stephen P Watson

doi:10.1016/j.bmcl.2009.11.032

The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2

Bioorg Med Chem Lett. 2010 Jan 15;20(2):759-62. doi: 10.1016/j.bmcl.2009.11.032. Epub 2009 Nov 26.

Affiliation

¹ GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, UK.

PMID: 20005096
DOI: 10.1016/j.bmcl.2009.11.032

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.

MeSH terms

Administration, Oral
Allosteric Regulation
Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacology
Dopamine / metabolism
High-Throughput Screening Assays
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology
Rats
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship
Synaptic Potentials / drug effects

Substances

Benzimidazoles
GSK 1331258
GSK 1331268
Piperazines
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor 2
Dopamine