Article,
Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists
Affiliations
- [1] Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen O, Denmark [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
- [2] Lophora, DK-2920 Copenhagen, Denmark [NORA names: Miscellaneous; Denmark; Europe, EU; Nordic; OECD];
- [3] Latvian Inst Organ Synth, LV-1006 Riga, Latvia [NORA names: Latvia; Europe, EU; OECD]
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.