Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists. J Med Chem 2016 Dec 08;59(23):10601-10618
Date
11/03/2016Pubmed ID
27805392Pubmed Central ID
PMC5148701DOI
10.1021/acs.jmedchem.6b01208Scopus ID
2-s2.0-85003632910 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
Biased ligands (also known as functionally selective ligands) of G protein-coupled receptors are valuable tools for dissecting the roles of G protein-dependent and independent signaling pathways in health and disease. Biased ligands have also been increasingly pursued by the biomedical community as promising therapeutics with improved efficacy and reduced side effects compared with unbiased ligands. We previously discovered first-in-class β-arrestin-biased agonists of dopamine D2 receptor (D2R) by extensively exploring multiple regions of aripiprazole, a balanced D2R agonist. In our continuing efforts to identify biased agonists of D2R, we unexpectedly discovered a G protein-biased agonist of D2R, compound 1, which is the first G protein-biased D2R agonist from the aripiprazole scaffold. We designed and synthesized novel analogues to explore two regions of 1 and conducted structure-functional selectivity relationship (SFSR) studies. Here we report the discovery of 1, findings from our SFSR studies, and characterization of novel G protein-biased D2R agonists.
Author List
Chen X, McCorvy JD, Fischer MG, Butler KV, Shen Y, Roth BL, Jin JAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AripiprazoleDose-Response Relationship, Drug
Drug Discovery
GTP-Binding Proteins
HEK293 Cells
Humans
Ligands
Molecular Structure
Receptors, Dopamine D2
Structure-Activity Relationship
