Structure-Guided Design of Novel 5-HT 2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects
Rongyan Li, Hong Yan, Yujin Chen, Yangyang Liu, Lingjie Tang, Jing Yu, Junjun Liu, Huan Wang, Sheng Wang, Jianjun Cheng
Journal of Medicinal Chemistry October 14, 2025 DOI: 10.1021/acs.jmedchem.5c02045 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | compound 28c |
| Topics | Serotonin |
| Citations | 1 |
| Key points | Compound 28c, a novel 5-HT2A partial agonist, exhibited antidepressant effects in the mouse tail-suspension test without inducing head-twitch responses. |
Abstract
Depression is primarily treated with selective serotonin reuptake inhibitors (SSRIs), which are limited by delayed onset of effects and low rates of remission. Recent studies showed that serotonergic psychedelics such as psilocybin can reduce depressive symptoms both rapidly and enduringly. Such effects have been associated with the activation of the serotonin 2A (5-HT2A) receptor in the central nervous system, which has prompted medicinal chemistry studies of novel 5-HT2A agonists. In this study, we designed and synthesized novel 5-HT2A partial agonists based on the structures of the antipsychotic drug aripiprazole and our previously reported lead compound IHCH-7086. Two series of new compounds were synthesized, a number of which exhibited potent 5-HT2A partial agonist activity in G protein coupling and β-arrestin2 recruitment assays. Compound 28c exhibited antidepressant effects in the mouse tail-suspension test without inducing head-twitch responses, supplementing the growing reservoir of nonhallucinogenic 5-HT2A agonists.
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
Cites 20
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 15 more in the library