Molecular Pharmacology of Dopamine Receptors: Structure, Function, and Therapeutic Implications.

Abstract

Dopamine receptors (DRs) mediate central and peripheral dopaminergic signaling and remain major therapeutic targets in movement disorders, psychiatric disease, and endocrine dysfunction. Despite decades of clinical use, existing DR-directed therapies still suffer from limited subtype selectivity, pathway-nonspecific engagement, and substantial adverse effects, reflecting an incomplete molecular understanding of receptor function. In this review, we examine recent advances in DR molecular pharmacology, focusing on how structural, pharmacological, and computational studies have clarified receptor activation, inverse agonism, transducer coupling, signaling bias, allosteric modulation, and ligand selectivity through analyses of inactive and active receptor states, including family-wide receptor-G protein complexes. We discuss how ligand-specific receptor conformations, transducer interactions, and membrane environment shape signaling output, help explain the diverse actions of dopaminergic ligands, and distinguish the activation trajectories of D1-like and D2-like receptors. We also consider how these advances, including insights into allosteric sites, transducer selectivity, and AI-assisted discovery, inform the development of more selective and precise dopaminergic therapies. Together, these developments are shifting the field from descriptive receptor pharmacology toward a mechanistic and structure-guided framework for therapeutic discovery.