Mechanistic Basis for 5-HT2AR Over 5-HT2BR Activation
Lingjie Tang, Xin Ji, Yumeng Wang, Dongmei Cao, Huiqiong Li, Licong He, Jianjun Cheng, Sheng Wang
Nature Communications September 17, 2026 DOI: 10.1038/s41467-026-77659-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key points | The authors report that steric and conformational constraints in the side-extended and extended binding pockets of 5-HT2AR and 5-HT2BR determine ligand orientation and signaling. They designed derivatives that reinforce 5-HT2AR activation while limiting 5-HT2BR activity, and cryo-EM structures with IHCH-2330, a selective 5-HT2AR agonist and 5-HT2BR antagonist, confirm this principle. They propose this as a rational framework for engineering safer, functionally selective serotonergic compounds. |
Abstract
Selective 5-HT2AR agonism without 5-HT2BR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HT2AR and 5-HT2BR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we design derivatives across tryptamine and phenethylamine scaffolds that integrate SEP and EBP engagement with scaffold modification to reinforce 5-HT2AR activation while limiting 5-HT2BR activity. Cryo-EM structures of 5-HT2AR and 5-HT2BR bound to IHCH-2330, a selective 5-HT2AR agonist and 5-HT2BR antagonist, confirm the design principle. These findings show differential activation mechanisms between 5-HT2AR and 5-HT2BR and provide a rational framework for engineering safer, functionally selective serotonergic compounds, mitigating 5-HT2BR–mediated side effects while preserving therapeutic efficacy. This study explores structural principles of receptor selectivity and establishes a strategy for designing selective 5-HT2AR agonists while reducing 5-HT2BR-associated valvulopathy risk.
Comparable studies
Other theoretical and historical papers on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics as Medicines: An Emerging New Paradigm General population | 2016 | Theoretical or philosophical paper | |
| Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate | 2018 | Theoretical or philosophical paper | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Dreams, Hallucinogenic Drug States, and Schizophrenia: A Psychological and Biological Comparison | 1983 | Theoretical or philosophical paper | |
| Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cites 28
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Long-term follow-up of psilocybin-facilitated smoking cessation The American Journal of Drug and Alcohol Abuse July 21, 2016
and 23 more in the library