Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists

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.