Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology.
Michał K Jastrzębski, Piotr Wójcik, Angelika Grudzińska, Giorgia Andreozzi, Tommaso Vetrò, Ayesha Asim, Akanksha Mudgal, Jakub Czapiński, Tomasz M Wróbel, Damian Bartuzi, Katarzyna M Targowska-Duda, Agnieszka A. Kaczor
Acta Pharmaceutica Sinica B September 1, 2025 DOI: 10.1016/j.apsb.2025.07.002 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Biased agonism Biased signaling G protein-coupled receptors Mental health disorders Psychedelics |
| Key findings | Biased agonism at the 5-HT2A receptor may enable therapeutic effects for depression and anxiety without hallucinations, and novel biased ligands show selective pathway activation. |
Abstract
G protein-coupled receptors (GPCRs) represent key drug targets, with approximately 30%-40% of all medications acting on these receptors. Recent advancements have uncovered the complexity of GPCR signaling, including biased signaling, which allows selective activation of specific intracellular pathways-primarily mediated by G proteins and β-arrestins. Among aminergic GPCRs, the serotonin 5-HT2A receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes, such as hallucinations, through biased agonism. This review delivers a comprehensive overview of 5-HT2A receptor-biased signaling and its significance in developing safer mental health therapeutics, particularly for depression and anxiety. We provide a critical evaluation of methodologies for assessing biased signaling, spanning from traditional radioligand binding assays to advanced biosensor technologies. Furthermore, we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling. We also highlight novel biased ligands with selective pathway activation, presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects. Additionally, we explore the 5-HT2A receptor's role in memory processes and stress response regulation. Ultimately, advancing our understanding of 5-HT2A receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies, maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
Cited by 2
- Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics. ACS Chemical Neuroscience June 17, 2026
- Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation. Neuroscience & Biobehavioral Reviews July 1, 2026
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