Development of Structure-Activity Relationships for a G protein-Biased Agonist of the D2 Dopamine Receptor

We previously published the discovery of a highly efficacious, functionally biased D2 dopamine receptor (D2R) agonist (MLS1547) that can selectively activate G protein signaling while blocking β-arrestin recruitment. In the interest of understanding the basis for its bias, the signaling properties of 23 MLS1547 analogs were characterized, which ranged from highly biased to unbiased. These results provided the basis for development of structure-activity relationships using pharmacophore modeling and molecular docking analyses. Subsequently, 69 additional MLS1547 analogs were tested for both β-arrestin and G protein signaling, which refined our model of the structural basis for G protein bias. We have confirmed that a hydrophobic feature, like the chloro group at C5 of MLS1547 is required for G protein-biased signaling. A hydroxyl group para to the C5 group also correlates with strong biased signaling. Replacing the 2-pyridyl group with other nitrogen heterocycles alters the nitrogen basicity, and has a mor...