Binding affinities for histamine receptors 1 to 4: Systematic comparison of ligands from the Psychoactive Drug Screening Program K(i) database and International Union of Basic and Clinical Pharmacology/British Pharmacological Society Guide to Pharmacology

Mol Pharmacol. 2026 Jun 12;108(7):100139. doi: 10.1016/j.molpha.2026.100139. Online ahead of print.

ABSTRACT

Histamine receptors (H₁R-H₄R) are G protein-coupled receptors with large physiological and therapeutic relevance. Despite extensive research, a systematic and cross-database overview of ligands is missing. This review integrates 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, both having different scopes and curation principles, and evaluates concordance of H_xR ligands across databases and experimental systems. Binding affinities (K_i) for 302 ligands targeting recombinant human H_xR were extracted from the PDSP K_i database (accessed January 2026) and converted to pK_i. A total of 302 ligands with relevant binding affinities were identified, including approved drugs and experimental compounds. Functional annotations and further binding affinities were retrieved from the IUPHAR/BPS Guide to Pharmacology and complementary literature, revealing missing or incomplete functional characterization for 69 ligands. Although most ligands were selective for a single H_xR, others displayed multireceptor affinity. Cross-database comparisons found limited overlap in ligands, differences in primary literature, and pK_i deviations. Comparisons with native human tissues and nonhuman species demonstrated substantial variability, with deviations of up to pK_i 4.2 in human brain tissues and up to pK_i 3.2 across species. This database-driven analysis highlights strengths and limitations of the PDSP K_i database (broad data aggregation) and the IUPHAR/BPS Guide to Pharmacology (curated representative selection). Although together they provide extensive coverage of H_xR ligands, incomplete overlap and selective data inclusion limit direct comparability and may give the impression of missing data despite substantial experimental data. Systematic integration is essential to improve data reliability, summarize knowledge, and support future drug development. SIGNIFICANCE STATEMENT: This review provides a systematic overview of ligand binding affinities and functional profiles across all 4 H_xR. It integrates data from the PDSP K_i database and the IUPHAR/ BPS Guide to Pharmacology and compares recombinant human H_xR with native tissues and several species. Substantial data gaps, inconsistencies, and context-dependent variability are revealed. The PDSP K_i database has large potential for use in scientific research and in the support of drug development.

PMID:42391979 | DOI:10.1016/j.molpha.2026.100139