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

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 G_S 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 G_S 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.