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.