Medications referred to as antidepressants target the serotonin transporter in nerve cells and are among the most commonly prescribed drugs worldwide, but are often associated with significant side effects. In a recent study, a research group led by Thomas Stockner of the Medical University of Vienna identified the fundamental principles of serotonin transport, laying the groundwork for the development of novel medicines with improved selectivity and fewer adverse effects. The findings were recently published in the esteemed journal „Nature Communications.“
While the desired effects of drugs are brought about by interacting with relevant target structures, the undesired side effects are often attributed to lack of selectivity, leading to interactions with other target structures. Accordingly, developing drugs capable of differentiating between different physiologically relevant targets (e.g., transporters and receptors) is a challenge in research. A team led by Ralph Gradisch, under the supervision of Thomas Stockner at the Center for Physiology and Pharmacology of the Medical University of Vienna, set out to find a way to increase selectivity for the serotonin transporter and simultaneously reduce interactions with other targets in neurons in the brain. In collaboration with the research group of Marko Mihovilovic from the Institute of Applied Synthesis Chemistry at the Vienna University of Technology, the researchers discovered the underlying principles behind how the serotonin transporter recognizes the neurotransmitter serotonin through the synthesis of serotonin-related molecules, deciphering the requirements for the transport of this messenger substance.
Regulating Emotions with Serotonin
Neurotransmitters, also referred to as neurotransmitters, act as „gatekeepers“ for information between nerve cells (neurons). The neurotransmitter serotonin, also known as one of the „feel-good hormones,“ is associated with positive emotions as it plays a key role in regulating moods and calmness. Low serotonin levels have been linked to mental illnesses such as depression, anxiety, and obsessive-compulsive disorder. Medications targeting the serotonin transporter are among the most commonly prescribed drugs worldwide. Blocking the serotonin transporter with serotonin reuptake inhibitors increases the concentration of the neurotransmitter in the synaptic cleft between nerve cells, helping patients alleviate the burden of their illness.
Deciphering the Steps Down to the Smallest Detail
The complex steps of serotonin transport were described in the study at the level of individual molecules, down to the smallest detail.
It was the tailored combination of chemical synthesis with methods of experimental and computer-assisted pharmacology that enabled these research findings.
Ralph Gradisch, Lead Author
„Our results reveal the key forces and interactions at play to initiate the transport of serotonin. This could have laid the groundwork for new types of molecules, potentially enabling the development of medications that target serotonin much more precisely,“ summarizes study leader Thomas Stockner the significance of the findings.
Medical University of Vienna
Gradisch, R., et al. (2024). Ligand coupling mechanism of the human serotonin transporter distinguishes substrates from inhibitors. Nature Communications. doi.org/10.1038/s41467-023-44637-6.