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High‐Throughput Screening for Novel Modulators of the D 1 Dopamine Receptor
Author(s) -
Conroy Jennie L.,
Hazelwood Lisa A.,
Free R. Benjamin,
Roof Rebecca A.,
Furman Cheryse A.,
Titus Steven A.,
Southall Noel,
Ferrer Marc,
Sibley David R.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.801.3
Dopamine is a critically important neurotransmitter in the CNS and peripheral nervous system. The D 1 dopamine receptor (DAR) plays an important role in cognition, reward and reinforcement, learning and memory, and the regulation of movement. D 1 ‐selective agents may prove beneficial in the treatment of many neuropsychiatric disorders, including Parkinson's disease. However, direct D 1 stimulation produces rapid desensitization and finding a truly D 1 ‐selective agonist has proven difficult due to high sequence similarities among the DARs. Another approach to receptor selectivity is to identify allosteric modulators that bind to less conserved sites on the receptor. Currently, we are using a high throughput screening (HTS) approach, which utilizes a cell line expressing the D 1 DAR coupled to G15 resulting in a robust Ca 2+ signal upon receptor stimulation, to identify novel D 1 ‐selective modulators. Through the NIH Molecular Libraries Program, a 370,000+ small molecule library is being screened to identify allosteric agonists, as well as positive and negative allosteric modulators. From this screen, hit molecules from each class will be chosen for further study. Secondary assays, screens on parental cell lines, and counter screens on other DARS will be used to evaluate activity and receptor selectivity of the compounds identified, and to aid in identifying novel D 1 allosteric ligands.