Structure–Functional Selectivity Relationship Studies of β-Arrestin-Biased Dopamine D 2 Receptor Agonists

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and non-canonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side-effects of drugs. However, few such ligands have been created and very little purposeful attention has been devoted to studying what we term: ‘structure-functional selectivity relationships’ (SFSR). We recently disclosed the first β-arrestin-biased dopamine D2 receptor (D2R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D2R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered