title: Identification of metabotropic glutamate receptor antagonists using an automated high-throughput screening system.
abstract: Antagonists to the human metabotropic glutamate receptor subtype 5a(mGluR(5a)) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and Parkinson's disease. To discover novel antagonists to the mGluR(5a), a functional assay measuring agonist-induced intracellular calcium release was developed. The assay was used for the high-throughput screening of a large collection of compounds in single wells using a fully automated robotic platform. Primary high-throughput screening hits were subjected to a combination of data analysis and counterscreening assays to identify several compounds with both efficacy and selectivity for the metabotropic glutamate receptor target.
authors.affiliation: Department of Automated Biotechnology, Merck Research Laboratories, North Wales, Pennsylvania 19454, USA. peter_hodder@merck.com
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Jason
authors.initials: J
authors.lastname: Cassaday
authors.forename: Richard
authors.initials: R
authors.lastname: Peltier
authors.forename: Kurtis
authors.initials: K
authors.lastname: Berry
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Bradley
authors.initials: B
authors.lastname: Feuston
authors.forename: Chris
authors.initials: C
authors.lastname: Culberson
authors.forename: Leo
authors.initials: L
authors.lastname: Bleicher
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Chris
authors.initials: C
authors.lastname: Bayly
authors.forename: Carla
authors.initials: C
authors.lastname: Suto
authors.forename: Mark
authors.initials: M
authors.lastname: Varney
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
mesh_terms: D002118:Calcium / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000032:analysis / Q000494:pharmacology*; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000737:chemistry; D005470:Fluorometry / Q000295:instrumentation / Q000379:methods*; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D010784:Photomicrography; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D014162:Transfection
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D002118:Calcium