Neuropharmacological Potential of Olfactory Receptors: Integrative Structural Insights for Novel Therapeutic...

The human olfactory system senses an exceptionally wide variety of odorant molecules by utilizing olfactory receptors (ORs), which are a very extensive and diverse family of genes in the human genome. These receptors belong to the Class A category of G-protein-linked receptor (GPCR) superfamily and share standard structural characteristics supporting neuromodulatory signaling. Although the past also teaches that ORs have long been investigated within the framework of odor detection, growing evidence suggests that their biological functions are much broader than traditional olfaction and that they are associated with neurodevelopment, mood regulation, and neuroimmune communication. Recent developments in artificial intelligence-based structure prediction, primarily AlphaFold2 (AF2), and cryo-electron microscopy (cryo-EM) have enabled the creation of stable, high-confidence structural models of ORs. These models reveal preserved transmembrane motifs with significant diversity in the extracellular loop regions, which are hallmark features of these themes that play a significant role in ligand recognition and downstream signal transduction. Consequently, ORs are now more susceptible to ligand docking, receptor deorphanization, and structure-directed pharmacological analysis. This study presents a review of existing structural and functional knowledge of OR biology in this review, especially its expanding applicability in neuro-pharmacology. External OR expression and signaling, such as in the brain, gastrointestinal tract, and other peripheral tissues, have been demonstrated to modify activities, such as serotonin release, wound healing, and reproductive chemotaxis. These results create a larger functional scheme of ORs that overlaps with pathways involved in neurodegeneration, inflammatory, metabolic control, and chemosensory integration. Translationally, this widened perspective is the place where OR-based biosensors, genotype-informed modulators, and exploratory therapeutic approaches that capitalize on receptor diversity may be developed. Simultaneously, discovery pipelines are being recon-figured by the combination of structural modeling, high-throughput ligand screening, and biased GPCR pharmacology to allow more rational approaches to drug design. Despite these developments, critical issues remain, including insufficient ligand annotation, receptor promiscuity, pseudo-gene classification, and context-dependent tissue-to-tissue signaling. Collectively, the demonstration that positioning ORs can be mechanistically tractable GPCRs with extensive physiological significance underscores their use as actionable neuropharmacological targets. Further optimization of structural models, growth of ligand libraries, and standardization of functional assays will play a key role in connecting chemosensory biology with precision medicine and in further applications to diagnostic therapy and biomarker development.