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

Summary

Psychedelics show promise for mental health, influencing behavior via neurotransmitter receptor influence on behavior. Their pharmacology involves serotonin agonist activity at the 5-HT receptor. Through careful chemistry and chemical synthesis, a new class of serotonin agonists, 2,5-dimethoxyphenylpiperidines, has been discovered. Structure–activity relationship investigations, considering stereochemistry, identified LPH-5 as a selective 5-HT2A receptor agonist. This advances drug studies by providing new tools to understand how serotonin signaling affects the brain.

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.

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