A High-Throughput Small-Molecule Ligand Screen Targeted to Agonists and Antagonists of the G-Protein-Coupled Receptor GPR54
| Autor: | Eli R. Schuman, Marcie A. Glicksman, Jake Ni, William F. Crowley, Maria Burnett, Ursula B. Kaiser, Wendy Kuohung, Deepa Mukhtyar |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Agonist
medicine.drug_class Inositol Phosphates High-throughput screening Cell CHO Cells Biology Pharmacology Ligands Biochemistry Article Receptors G-Protein-Coupled Analytical Chemistry Cricetulus Cricetinae medicine Animals Humans Extracellular Signal-Regulated MAP Kinases Inositol phosphate Receptor chemistry.chemical_classification Chinese hamster ovary cell In vitro toxicology High-Throughput Screening Assays medicine.anatomical_structure chemistry Molecular Medicine Signal transduction hormones hormone substitutes and hormone antagonists Receptors Kisspeptin-1 Biotechnology |
| Zdroj: | SLAS Discovery. 15:508-517 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/1087057110369701 |
| Popis: | Recent data have shown that the G-protein-coupled receptor GPR54 (also known as KiSS-1 receptor) regulates GnRH release from the hypothalamus. This essential role of GPR54 in controlling the hypothalamic-pituitary-gonadal axis makes it an attractive target for therapeutic intervention in reproductive and cancer medicine. Currently, there are no small-molecule modulators of GPR54 function for experimental or clinical use. To identify small-molecule compounds that modify GPR54 signal transduction, the authors have adapted a cell-based functional assay for high-throughput screening (HTS) using a commercially available homogeneous time-resolved fluorescence assay for inositol phosphate accumulation. They generated stable Chinese hamster ovary cell transfectants that express human GPR54 for use in this assay. After optimization in an automated HTS environment, they screened a library of 110,000 small-molecule compounds using 2 protocols, one to identify agonists and one to identify antagonists. Hits obtained in the primary screen were confirmed to be active in secondary in vitro assays. Compounds identified as agonists or antagonists from HTS and secondary screening will be characterized to identify agents with the potential to be developed as novel orally active agents to treat hormone-dependent disorders such as abnormal puberty, infertility, endometriosis, and sex steroid-dependent tumors. |
| Databáze: | OpenAIRE |
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