ACS Chem Neurosci. 2025 Aug 13. doi: 10.1021/acschemneuro.5c00443. Online ahead of print.
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.
PMID:40802711 | DOI:10.1021/acschemneuro.5c00443
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