Structure–Functional
Selectivity Relationship
Studies of β‑Arrestin-Biased Dopamine D<sub>2</sub> Receptor
Agonists
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Abstract
Functionally selective G protein-coupled receptor (GPCR)
ligands,
which differentially modulate canonical and noncanonical 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 D<sub>2</sub> receptor (D<sub>2</sub>R) agonists UNC9975 (<b>44</b>) and UNC9994 (<b>36</b>), 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 D<sub>2</sub>R agonists. These studies
provide a successful proof-of-concept for how functionally selective
ligands can be discovered