Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology.
10.1016/j.apsb.2025.07.002
- Author:
Michał K JASTRZĘBSKI
1
;
Piotr WÓJCIK
1
;
Angelika GRUDZIŃSKA
1
;
Giorgia ANDREOZZI
2
;
Tommaso VETRÒ
3
;
Ayesha ASIM
1
;
Akanksha MUDGAL
4
;
Jakub CZAPIŃSKI
5
;
Tomasz M WRÓBEL
1
;
Damian BARTUZI
1
;
Katarzyna M TARGOWSKA-DUDA
4
;
Agnieszka A KACZOR
1
Author Information
1. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, Lublin PL-20093, Poland.
2. Department of Pharmacy, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
3. Department of Drug Science and Technology, University of Turin, Turin 10125, Italy.
4. Department of Biopharmacy, Faculty of Pharmacy, Medical University of Lublin, Lublin PL-20093, Poland.
5. Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin PL-20093, Poland.
- Publication Type:Review
- Keywords:
5-HT2A receptor;
Biased agonism;
Biased signaling;
G protein-coupled receptors;
Mental health disorders;
Psychedelics
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4438-4455
- CountryChina
- Language:English
-
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.
