A Cascade of Acid-Promoted C–O Bond Cleavage and Redox Reactions: From Oxa-Bridged Benzazepines to Benzazepinones

A sequence of C–O bond cleavage and redox reactions in oxa-bridged azepines was realized under acid promoted conditions. This protocol provides an atom-economical and straightforward approach to access benzo­[<i>b</i>]­azepin-5­(2<i>H</i>)-ones in high yields. The formal synthesis of tolvaptan was achieved by exploiting this new transformation

Structure–Functional Selectivity Relationship Studies of β‑Arrestin-Biased Dopamine D₂ Receptor Agonists

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 D₂ receptor (D₂R) 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 D₂R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered