Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and -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-HTR), 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-HTR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue ()-] as a selective 5-HTR agonist with desirable drug-like properties.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11089506PMC
http://dx.doi.org/10.1021/acs.jmedchem.4c00082DOI Listing

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