Comparative analysis of ligand binding affinities and functional profiles at recombinant human β-adrenergic receptor...

β-Adrenergic receptors (β_xAR) are G protein-coupled receptors with major physiological and therapeutic relevance in cardiovascular and respiratory conditions. Although numerous ligands have been investigated, binding affinities and functional annotations remain incomplete and fragmented across databases. This review systematically integrates ligand binding affinities and functional profiles at recombinant human β_xAR from the Psychoactive Drug Screening Program K_i database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS), with a focus on clinically important ligands, receptor selectivity, and characteristic patterns. Database agreement, affinity patterns, stereoisomer-specific information and concordance with primary literature are evaluated. In total, 156 ligands with pK_i ≥ 5 were collected. Median pK_i values were 6.6 for hβ₁AR, 6.15 for hβ₂AR, and 5.8 for hβ₃AR. A pronounced overlap between hβ₁AR and hβ₂AR was observed, reflected in similar median affinities and shared ligand profiles, whereas hβ₃AR showed narrower data coverage and a more distinct affinity distribution. Most ligands were listed for more than 1 hβ_xAR, and 37 ligands had binding data for all 3 hβ_xAR. Functional characterization was available for 90 ligands, whereas 61 lacked annotations. Database comparison revealed low overlap in ligand listings (28.8%). Stereoisomer data were highly incomplete, and in several cases, affinity-based stereoisomer comparisons differed from literature-reported stereoisomeric superiority. Summarized, substantial similarity between hβ₁AR and hβ₂AR ligand binding patterns is observed, whereas hβ₃AR appears less extensively characterized. Considerable fragmentation, incomplete receptor profiling and methodological heterogeneity limit the evaluation of receptor and ligand characteristics. Binding affinity and functional behavior must be interpreted as context-dependent parameters influenced by experimental systems, G protein coupling conditions and stereochemical specification. SIGNIFICANCE STATEMENT: This analysis systematically integrates ligand binding affinities and functional labels at recombinant human β_xAR from the Psychoactive Drug Screening Program (PDSP) K_i database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, providing a structured and comprehensive overview of ligand profiles. It identifies substantial data fragmentation, incomplete receptor and stereoisomer characterization, and limited concordance between databases. For clinically relevant ligands, it was demonstrated that therapeutic subtype classification does not always correspond to strict affinity-based receptor selectivity.