# Regulating dopamine transport through allosteric modulation - Functional and Behavioral Studies

> **NIH NIH R01** · DREXEL UNIVERSITY · 2024 · $678,663

## Abstract

The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET)
and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission
through the reuptake of their respective neurotransmitters. MATs are targets for the treatment of numerous
neurological disorders such as depression, anxiety, and attention deficit hyperactivity disorder (ADHD), and they
serve as target proteins for major drugs of abuse such as amphetamine and cocaine. The continuing need for
therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason
to further our understanding of transporter function and to identify novel ways of targeting them.
This project builds on our recent discovery of an allosteric site (A2) within the MATs that can serve as a target
site for modulating their activity. Previous experiments in our group targeted the allosteric A2 site in SERT and
identified molecules that interact with this site and display remarkable transporter-modulating activities. These
compounds have revealed that engaging this site modulate MAT activity in entirely novel ways, including
affecting the interaction with transporter ligands such as the selective serotonin reuptake inhibitors (SSRIs) and
psychostimulants. In corresponding experiments on DAT, we have identified compounds, KM822 and sydnocarb
among others, that similarly modifies DAT function. We find that these compounds interfere with the interaction
of DAT with exogenous ligands and attenuates psychostimulant-elicited behaviors in rodents. Computational
simulations further support the premise that compounds interacting with the allosteric A2 site can allow transport
while interfering with the interaction of the transporter with exogenous ligands like cocaine.
The overarching hypothesis of this project is that the specific engagement of the allosteric site in DAT will provide
valuable information regarding mechanisms of the dopamine transport process and could provide novel
therapeutic avenues for developing DAT-based medications. We propose to pursue this idea by further
characterizing the compounds to study allosteric modulation of DAT. We will in Aim 1 elucidate mechanisms of
allosteric transporter modulation through computational modelling and molecular simulations coupled with
functional and biochemical studies. In aim 2 we will evaluate the in vivo utility of the compounds by examining
their effects on psychostimulant-elicited behaviors in rodents. Finally, in Aim 3, we will employ structure-based
design to identify A2-specific compounds with improved properties. Consequently, the successful completion of
this project will result in the development of novel ligands of DAT that can be employed as experimental tools to
provide critical mechanistic information regarding allosteric transporter modulation. Furthermore, the design and
development of novel allosteric modulators of DAT will enable a s...

## Key facts

- **NIH application ID:** 10800883
- **Project number:** 1R01DA057982-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Ole Valente Mortensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,663
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800883

## Citation

> US National Institutes of Health, RePORTER application 10800883, Regulating dopamine transport through allosteric modulation - Functional and Behavioral Studies (1R01DA057982-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10800883. Licensed CC0.

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