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. 2025 May 29;8(6):1791-1803.
doi: 10.1021/acsptsci.5c00208. eCollection 2025 Jun 13.

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

Anders A Jensen  1   2 , Claudia R Cecchi  3 , Meghan Hibicke  4 , Astrid H Bach  3 , Erik Kaadt  3 , Emil Märcher-Rørsted  1   2 , Charles D Nichols  4 , Betina Elfving  3 , Jesper L Kristensen  1   2
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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

Anders A Jensen et al. ACS Pharmacol Transl Sci. .

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.

Keywords: 5-HT2A receptor; LPH-5; behavioral studies; classical psychedelics; depression; subtype-selective.

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