Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants
Wenwen Duan, Dongmei Cao, Sheng Wang, Jianjun Cheng
Chemical Reviews November 30, 2023 DOI: 10.1021/acs.chemrev.3c00375 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | LSD Psilocybin Serotonin |
| Keywords | Hallucinogen Pharmacology Drug Functional selectivity 5-HT Receptor |
| Citations | 62 |
| Key findings | Rationally designed 5-HT2AR agonists with improved subtype selectivity and signaling bias properties could serve as safer, potentially nonhallucinogenic antidepressants. |
Abstract
Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.
Comparable studies
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Citations in the library
Cited by 41
- Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience February 27, 2024
- Early psilocybin intervention alleviates behavioral despair and cognitive impairment in stressed Wistar rats Progress in Neuro-Psychopharmacology and Biological Psychiatry 2025
- Plant-derived compounds and neurodegenerative diseases: Different mechanisms of action with therapeutic potential. Neuroscience February 6, 2025
- Predicting the Hallucinogenic Potential of Molecules Using Artificial Intelligence ACS Chemical Neuroscience August 2, 2024
- Neuropsychopharmacology of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists. British Journal of Pharmacology May 23, 2025
and 36 more in the library
Cites 160
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and 155 more in the library