Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists
Karla Frydenvang, Emil Märcher-Rørsted, Anders A. Jensen, Gints Šmits, Jesper L. Kristensen
Journal of Medicinal Chemistry April 22, 2024 DOI: 10.1021/acs.jmedchem.4c00082 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | Pharmacology 5-HT Receptor Structure–activity relationship Serotonin agonist Stereochemistry |
| Citations | 7 |
| Key points | Proposes that the discovery of 2,5-dimethoxyphenylpiperidines as selective 5-HT2AR agonists, particularly LPH-5, provides a tool to investigate the receptor's role in persistent therapeutic effects of psychedelics. |
Abstract
Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HT2AR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HT2AR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with desirable drug-like properties.
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
Cited by 7
- Chemistry/structural biology of psychedelic drugs and their receptor(s). British Journal of Pharmacology October 2, 2024
- The Selective 5HT2A Receptor Agonist, 25CN-NBOH Exerts Excitatory and Inhibitory Cellular Actions on Mouse Medial Prefrontal Cortical Neurons. Synapse March 1, 2025
- The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors. Molecular Pharmacology 2026
- The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents ACS Pharmacology & Translational Science May 29, 2025
- Structure-based design of subtype-selective psychedelic analogs Nature Communications September 17, 2026
and 2 more in the library
Cites 27
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
and 22 more in the library