Identification of metabotropic glutamate receptor antagonists using an automated high-throughput screening system.
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.
Hodder
Peter
P
Department of Automated Biotechnology, Merck Research Laboratories, North Wales, Pennsylvania 19454, USA. peter_hodder@merck.com
Cassaday
Jason
J
Peltier
Richard
R
Berry
Kurtis
K
Inglese
James
J
Feuston
Bradley
B
Culberson
Chris
C
Bleicher
Leo
L
Cosford
Nicholas D P
ND
Bayly
Chris
C
Suto
Carla
C
Varney
Mark
M
Strulovici
Berta
B
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
D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D002118:Calcium