Depression affects millions globally and current treatments are not fully curative. Recent insights into the structure and function of the serotonin 2A (5-HT2A) receptor have enabled the design of new antidepressant compounds. This review summarizes the role of 5-HT2A receptor signaling modulators in depression treatment, describes the receptor's structural and physiological features, and overviews recent virtual screening campaigns that identified novel 5-HT2A receptor ligands, along with data on newly synthesized ligands acting through this protein.
G protein-coupled receptors (GPCRs) are targets for many drugs, and recent work has revealed biased signaling, where a receptor selectively activates certain intracellular pathways (G proteins or β-arrestins). The serotonin 5-HT2A receptor is of particular interest because biased agonism might produce therapeutic benefits for depression and anxiety without causing hallucinations. This review covers methods for measuring biased signaling, from traditional binding assays to biosensors, and structural studies identifying key receptor residues. Novel biased ligands that activate only some pathways offer a path to antidepressant therapies without psychedelic effects. The 5-HT2A receptor also plays roles in memory and stress regulation. Understanding biased signaling could lead to safer GPCR-targeted psychiatric treatments.