Summary: Researchers have identified a compound, Lu AF60097, that binds to an allosteric site on the serotonin transporter (SERT) and may allow tricyclic antidepressants to be used at lower doses, potentially reducing the serious side effects associated with these drugs in severe depression.
Source: University of Copenhagen
About one in five Danes experience depression during their lifetime. For severe cases, tricyclic antidepressants are often more effective than medications used for mild to moderate depression, but their use is limited by significant and sometimes dangerous side effects.
Tricyclic antidepressants can provide powerful symptom relief, yet many patients discontinue treatment because of adverse effects that range from dry mouth and visual disturbances to weight gain, digestive problems, manic switches, and, in rare cases, life‑threatening cardiac complications. These side effects reduce adherence and leave many people with severe depression untreated.
Now, researchers at the Faculty of Health and Medical Sciences, University of Copenhagen, together with partners at Lundbeck A/S and the National Institutes of Health in Baltimore, report the discovery of a compound, Lu AF60097, that works by a different mechanism and could help mitigate these problems.
“We have identified a substance, Lu AF60097, that binds to an allosteric site on SERT and modulates its function rather than blocking it entirely. Combined with tricyclic antidepressants, this could allow for effective treatment with much lower doses of the classical drugs and therefore fewer side effects,” says Professor Claus Juul Løland from the Department of Neuroscience, Faculty of Health and Medical Sciences.
Therapeutic effect with fewer side effects
Serotonin is a key neurotransmitter involved in mood regulation. In severe depression, serotonin availability in the brain is often reduced. Many antidepressants work by preventing serotonin from being taken back up into nerve terminals, thereby increasing the amount available to signal between neurons.
Conventional antidepressants typically bind to the same central site on the serotonin transporter (SERT) as serotonin itself. Blocking this central binding site (S1) effectively stops serotonin reuptake but often requires relatively high drug concentrations, which can lead to the range of unwanted systemic effects seen with tricyclics.
Lu AF60097, by contrast, binds to a different region on SERT known as an allosteric or extracellular vestibule site (S2). Binding at this site alters the conformation of the transporter and modulates how the central site interacts with its ligands. This allosteric modulation enables the central antidepressant to bind more tightly and act more effectively at lower concentrations.
“In our experiments we showed that when Lu AF60097 binds the allosteric site while a tricyclic antidepressant occupies the central site, the antidepressant’s binding is potentiated. This suggests the same therapeutic effect can be achieved using much smaller doses of the tricyclic drug, potentially reducing dose‑dependent adverse effects,” explains Claus Juul Løland.
From concept to clinical drug
The team screened a large number of compounds from Lundbeck’s drug library across several rounds to identify a molecule with sufficient affinity for the allosteric site to allow pharmacological investigation. Lu AF60097 emerged as the first high‑affinity S2 ligand suitable for detailed study.
Laboratory and animal studies demonstrate that Lu AF60097 allosterically enhances imipramine binding at S1 and increases hippocampal serotonin levels in rats, indicating a meaningful pharmacological effect. These results validate the concept that S1 and S2 sites are functionally coupled and that high‑affinity allosteric modulators can potentiate classical SERT inhibitors.
However, translating this finding into a safe and effective human medication will require further development. The current studies establish that the mechanism works in cells and in animal models; the next steps are medicinal chemistry optimization, safety testing, and clinical trials to confirm efficacy and tolerability in people.
“We have taken an important first step by demonstrating the concept. If this approach proves successful in humans, it could lead to improved therapies for people with severe depression who cannot tolerate existing tricyclic antidepressants,” says the research team.
Source:
University of Copenhagen
Media contact:
Claus Juul Løland – University of Copenhagen
Image source:
Public domain
Original research (open access):
“The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter.” Per Plenge, Ara M. Abramyan, Gunnar Sørensen, Arne Mørk, Pia Weikop, Ulrik Gether, Benny Bang‑Andersen, Lei Shi & Claus J. Loland. Nature Communications. DOI: 10.1038/s41467-020-15292-y.
Abstract (summary)
The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake and is a primary target for many antidepressants. Structural studies have revealed two ligand binding pockets: the central S1 site and an extracellular S2 vestibule. Combined in vitro and in silico analyses indicate that ligands bound to S1 and S2 are allosterically coupled through protein conformational changes. Lu AF60097 is the first characterized high‑affinity S2 ligand; it allosterically potentiates binding at S1, inhibits SERT, and increases hippocampal serotonin in rats. This S1–S2 coupling mechanism offers a path for rational design of high‑affinity allosteric SERT inhibitors that could improve therapeutic outcomes by enabling lower doses of conventional antidepressants.