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
Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted, Betina Elfving, Anders A. Jensen, Cláudia R. Cecchi, Astrid H. Bach, Charles D. Nichols, Jesper L. Kristensen
ACS Pharmacology & Translational Science May 29, 2025 DOI: 10.1021/acsptsci.5c00208 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | LPH-5 |
| Topics | Serotonin |
| Keywords | Antidepressant Piperidine Agonist 5-HT Receptor Trifluoromethyl Pharmacology |
| Citations | 3 |
| Key points | Selective 5-HT2A receptor activation by LPH-5 produces antidepressant-like effects in rats. |
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.