Dual Modulation of 5-HT2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers.
Justin M Silverman, Michael Fiorillo, Jason Younkin, Charles B Jones, Jessica L Maltman, Isaac Herszenhorn, Anaceli Artigas, Jennifer T Wolstenholme, Małgorzata Dukat, Javier González-Maeso
ACS chemical neuroscience December 17, 2025 DOI: 10.1021/acschemneuro.5c00468 via PubMed
Summary
AI-generated from the abstractα-Ethyltryptamine (AET), a synthetic tryptamine once used as an antidepressant, acts through a dual mechanism involving both direct activation of the 5-HT2A receptor and indirect serotonin release via the serotonin transporter (SERT). In vitro, AET and its isomers displaced ketanserin from the 5-HT2A receptor with micromolar affinity, but only the S(+)-AET isomer showed weak partial agonist activity. In mice, all forms of AET produced a head-twitch response that was blocked by a 5-HT2A antagonist and also by fluoxetine, indicating that SERT-mediated serotonin release contributes to its behavioral effects. This dual pharmacology distinguishes AET from classical psychedelics and aligns it with MDMA-like compounds, suggesting potential for modulating mood and cognition.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | racemic AET R(-)-AET S(+)-AET fluoxetine DOI |
| Topics | Serotonin |
| Keywords | G protein-coupled receptor Head-twitch response Psychedelics Serotonin transporter |
| Citations | 1 |
| Key finding | AET's behavioral effects rely on both direct 5-HT2A receptor activation and indirect serotonergic potentiation via SERT, distinguishing it from classical psychedelics. |
Abstract
α-Ethyltryptamine (AET), a synthetic tryptamine formerly used as an antidepressant, has resurfaced as a compound of interest due to its structural and functional overlap with serotonergic psychedelics and entactogens. Here, we characterized the pharmacological properties of racemic AET and its optical isomers, R(-)-AET and S(+)-AET, focusing on their interactions with the serotonin (or 5-hydroxytryptamine) 5-HT2A receptor (5-HT2AR) and serotonin transporter (SERT). In vitro, all three compounds displaced [3H]ketanserin from 5-HT2AR with micromolar affinity; however, only S(+)-AET elicited weak partial agonist activity in calcium mobilization assays, an effect abolished by the 5-HT2AR antagonist volinanserin. In vivo, all forms of AET induced a dose-dependent effect on the head-twitch response (HTR) in mice, which was completely blocked by volinanserin, confirming the 5-HT2AR involvement. Notably, pretreatment with fluoxetine abolished AET-induced HTR without affecting responses to the classical psychedelic DOI, implicating SERT-mediated serotonin release in AET's mechanism of action. These findings indicate that AET's behavioral effects rely on a dual mechanism involving both direct 5-HT2AR activation and indirect serotonergic potentiation via SERT. This dual pharmacology distinguishes AET from classical psychedelics and places it within a unique niche alongside MDMA-like serotonergic agents, highlighting the therapeutic and neuropsychiatric potential of AET isomers for modulating mood and cognition.