Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists

  • J Med Chem. 2024 May 9;67(9):7224-7244. doi: 10.1021/acs.jmedchem.4c00082.
Emil M Ro Rsted  1  2 ,  Anders A Jensen  1  2 ,  Gints Smits  3 ,  Karla Frydenvang  2 ,  Jesper L Kristensen  1  2
Affiliations
  • 1. Lophora, Charlottenlund, Copenhagen 2920, Denmark.
  • 2. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen Ø 2100, Denmark.
  • 3. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia.
PMID: 38648420 DOI: 10.1021/acs.jmedchem.4c00082
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.

Products