Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter.
Arabo A. Avanes, Hunter T Warren, Abinaya Senthil, David E. Olson
ACS Chemical Neuroscience September 3, 2025 DOI: 10.1021/acschemneuro.5c00443 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | SERT-transfected HEK293T cells |
| Intervention | UCD0820 |
| Topics | Ibogaine MDMA Serotonin |
| Keywords | Sert Ssri Fluoxetine Serotonin transporter Tropane |
| Citations | 2 |
| Key points | Several tropane compounds, including UCD0168 and UCD0820, potently modulate the serotonin transporter in ways similar to fluoxetine, MDMA, or noribogaine, demonstrating the tropane scaffold's potential for developing SERT modulators. |
Abstract
Tropane alkaloids and their derivatives represent a diverse class of small molecules with a broad range of therapeutic applications. Many tropanes regulate synaptic levels of neuromodulators by interacting with monoamine transporters such as dopamine (DAT) and serotonin (SERT) transporters. While DAT inhibition plays an important role in the addictive potential of tropanes such as cocaine, recent evidence suggests that SERT modulation may oppose the effects of DAT inhibition. Moreover, SERT modulators such as 3,4-methylenedioxymethamphetamine (MDMA), ibogaine, and selective-serotonin reuptake inhibitors (SSRIs) have demonstrated potential as treatments for a broad range of conditions, including depression, addiction, and post-traumatic stress disorder (PTSD). Here, we profiled a variety of structurally distinct subclasses of tropanes in SERT inhibition, efflux, and pharmacochaperone assays. We identified several compounds capable of potently modulating SERT in ways similar to those of fluoxetine, MDMA, or noribogaine. In particular, UCD0168 and UCD0820 emerged as potent SERT inhibitors that act as full and partial serotonin releasing agents (SRAs) in SERT-transfected HEK293T cells, respectively. Our work demonstrates that it is possible to use the tropane scaffold as a starting point for identifying both MDMA-like and noribogaine-like SERT modulators, and we provide several new tropane-containing hit structures for creating optimized therapeutics relying on SERT modulation.
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 18
- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine October 1, 2023
- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study PLoS One May 4, 2012
- 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Translational Psychiatry September 15, 2015
- The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. Journal of Biological Chemistry May 25, 2012
and 13 more in the library