Development of pH-Sensitive β‑Adrenergic Receptor Antagonists

G protein-coupled receptors (GPCRs) can trigger distinct signaling pathways depending on their localization. Because their appearance is not restricted, GPCRs can signal not only from the plasma membrane but also from internalized compartments. The pH of endosomes is significantly lower compared to the extracellular environment, and thus, location-biased ligands can be developed by carefully adjusting their physicochemical properties. This work describes the development of pH-sensitive β-adrenergic receptor antagonists with weak basicity, conferring enrichment in acidic compartments. Starting from FDA-approved β-blockers including bisoprolol, metoprolol, propranolol, and nebivolol, chemical synthesis, physicochemical studies, in vitro pharmacological investigations, and structure-activity relationship studies led to ligands with considerably higher potency at representative acidic pH values of 6 and 6.5 compared to a pH of 7.4, which is typical for ligand binding at the plasma membrane. Bis-fluorination in the beta position of nitrogen substituents was the most effective and led to pH-sensitive analogs of bisoprolol, metoprolol, and propranolol with 10- to 12-fold higher potencies at endosome-specific pH values. Because endosomal β-adrenergic receptors are suggested to be associated with heart hypertrophy and cardiac dysfunction, the newly developed ligands may serve as lead compounds for the development of powerful and safe cardioprotective drugs.