Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists.


Journal Article

G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood-brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands.

Full Text

Duke Authors

Cited Authors

  • Martini, ML; Liu, J; Ray, C; Yu, X; Huang, X-P; Urs, A; Urs, N; McCorvy, JD; Caron, MG; Roth, BL; Jin, J

Published Date

  • April 11, 2019

Published In

Volume / Issue

  • 62 / 7

Start / End Page

  • 3753 - 3772

PubMed ID

  • 30875219

Pubmed Central ID

  • 30875219

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.9b00351


  • eng

Conference Location

  • United States