title: A novel series of benzimidazole NR2B-selective NMDA receptor antagonists.
abstract: A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Davies
authors.forename: Matthew
authors.initials: M
authors.lastname: Crowe
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Lucas
authors.forename: Joanna
authors.initials: J
authors.lastname: Quinn
authors.forename: David D
authors.initials: DD
authors.lastname: Miller
authors.forename: Sara
authors.initials: S
authors.lastname: Pritchard
authors.forename: David
authors.initials: D
authors.lastname: Grose
authors.forename: Ezio
authors.initials: E
authors.lastname: Bettini
authors.forename: Novella
authors.initials: N
authors.lastname: Calcinaghi
authors.forename: Caterina
authors.initials: C
authors.lastname: Virginio
authors.forename: Lee
authors.initials: L
authors.lastname: Abberley
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Anton D
authors.initials: AD
authors.lastname: Michel
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
authors.forename: Neil D
authors.initials: ND
authors.lastname: Miller
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Gunthorpe
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D001562:Benzimidazoles; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate