ACS pharmacology & translational science
June 14, 2024
Richard A Glennon, Małgorzata Dukat
21 citations
The compound DOI, first synthesized in 1973, is a serotonin receptor agonist, specifically acting at 5-HT2 receptors in rat and human brain. It emerged from research on hallucinogenic agents and is now studied for potential therapeutic use in neuropsychiatric disorders such as treatment-resistant depression. This review traces the historical and current developments that made DOI a landmark agent in 5-HT2 receptor research.
Frontiers in pharmacology
January 1, 2023
Prithvi Hemanth, Pallavi Nistala, Vy T Nguyen et al.
4 citations
For a series of 13 compounds related to the psychedelic agent 2,5-DMA, rat brain 5-HT2 receptor affinities correlate strongly with human 5-HT2A (r = 0.942) and 5-HT2B (r = 0.916) affinities. Human 5-HT2A affinity also correlates with the lipophilicity of the 4-position substituent (r = 0.798). In functional assays, eight of ten compounds acted as agonists at the human 5-HT2B receptor, while two acted as antagonists. Human 5-HT2B affinity, but not agonist action, correlates with substituent lipophilicity (r = 0.750). Rat and human 5-HT2A affinity may approximate human 5-HT2B affinity but cannot predict agonist action. Some 2,5-DMA analogs on the clandestine market may pose cardiac valvulopathy risk with chronic use via h5-HT2B activation.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
ACS chemical neuroscience
December 17, 2025
Justin M Silverman, Michael Fiorillo, Jason Younkin et al.
1 citation
α-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.