The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents
Document Type
Article
Publication Date
5-29-2025
Publication Title
ACS Pharmacology and Translational Science
Abstract
Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2A receptor (5-HT2AR) with pronounced selectivity for 5-HT2AR over the related 5-HT2BR and 5-HT2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.
First Page
1791
Last Page
1803
PubMed ID
40534669
Volume
8
Issue
6
Recommended Citation
Jensen, Anders A.; Cecchi, Claudia R.; Hibicke, Meghan; Bach, Astrid H.; Kaadt, Erik; Märcher-Rørsted, Emil; Nichols, Charles D.; Elfving, Betina; and Kristensen, Jesper L., "The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents" (2025). School of Medicine Faculty Publications. 3854.
https://digitalscholar.lsuhsc.edu/som_facpubs/3854
10.1021/acsptsci.5c00208