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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 3
- The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors. Molecular Pharmacology 2026
- Psilocybin and Mental Health Outcomes: Scoping Review with ☸SAIMSARA SAIMSARA Journal June 15, 2026
- Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design Journal of Medicinal Chemistry September 25, 2025
Cites 36
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Global Street Food: la cocina de la calle Diseño interior 2009
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
and 31 more in the library