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.