Serotonin 2A (5-HT2A) receptor as evolving biological target: function, structure, ligands and role in the therapy of neuropsychiatric diseases

Abstract

The serotonin 5-HT_2A receptor is a G-protein-coupled receptor that plays a critical role in numerous physiological processes within the central nervous system. While it is essential for normal neurobiological function, dysregulation or aberrant signaling of the 5-HT_2A receptor has been implicated in the pathophysiology of various neuropsychiatric disorders. This review provides a comprehensive overview of the 5-HT_2A receptor, including its structure, function, ligand interactions, and therapeutic potential. Its molecular structure is detailed, with key binding domains highlighted that facilitate interactions with agonists, antagonists, and inverse agonists, influencing receptor activation and intracellular signaling pathways. The sites of 5-HT_2A receptor expression in both the central and peripheral nervous systems are also presented, and ligands are classified based on their interactions with the receptor. The receptor's role as a focal point in the treatment of psychiatric disorders such as schizophrenia and depression is examined, with emphasis placed on its modulation by atypical antipsychotics and emerging psychedelic-based therapies. Furthermore, its involvement in functional selectivity, biased agonism, and interactions with dopaminergic and glutamatergic systems is explored. Recent advancements in non-hallucinogenic 5-HT_2A receptor agonists and inverse agonists are also discussed, highlighting their potential for therapeutic intervention with improved safety profiles. The insights provided in this review contribute to a deeper understanding of 5-HT_2A receptors' role in neuropsychiatric disorders and support ongoing drug development efforts to optimize receptor-targeted therapies.