Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter.

Tropane alkaloids and their derivatives are a diverse group of small molecules with many therapeutic uses. Many tropanes affect dopamine and serotonin transporters in the brain. While blocking the dopamine transporter contributes to the addictive potential of tropanes like cocaine, modulating the serotonin transporter may counteract those effects. Serotonin transporter modulators such as MDMA, ibogaine, and SSRIs show promise for treating depression, addiction, and PTSD. This work profiled various tropane subclasses and identified compounds, notably UCD0168 and UCD0820, that potently modulate the serotonin transporter similarly to fluoxetine, MDMA, or noribogaine. UCD0168 acts as a full serotonin releasing agent, and UCD0820 as a partial one. The tropane scaffold can serve as a starting point for developing new serotonin transporter modulators.

Study at a glance

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.