Atomic view reveals how cariprazine binds the dopamine D3 receptor in the brain

A medicine developed in Hungary and now used by millions of people worldwide has yielded a new insight into how antipsychotic drugs work at the molecular level.

An international team led by researchers at the HUN-REN Research Centre for Natural Sciences has visualised, for the first time at atomic resolution, how cariprazine binds to the dopamine D3 receptor, one of its key targets in the brain. The researchers also used the resulting structural information to design new compounds that target the receptor more selectively. The study was published in Science Advances.

The findings provide a detailed molecular picture of a drug whose clinical effects have been known for years, but whose precise interaction with the D3 receptor had remained unseen. They could also provide a foundation for the more rational design of future medicines acting on the nervous system.

Unlike drugs that simply block or fully activate particular receptors, cariprazine acts as a partial agonist at dopamine D2 and D3 receptors. In other words, it activates them only partially or even inhibits depending on the dopamine levels in the brain. This allows it to rebalance dopaminergic signalling more subtly and with fewer side effects than earlier generations of antipsychotic drugs, an important feature of its clinical profile.

Receptors are proteins that recognise particular molecules and transmit signals into cells when those molecules bind. The dopamine D3 receptor is of particular interest as a drug target because it is found in brain regions and neural networks involved in mood-related processes, motivation and some cognitive functions.

Although cariprazine's pharmacological properties and clinical effects have long been characterised, researchers had not previously been able to see exactly how the molecule sits within the D3 receptor, or which of its molecular interactions determine the receptor's response.

The new study fills in that missing part of the picture.

Seeing the interaction atom by atom

The team combined high-resolution cryo-electron microscopy with pharmacological analyses and advanced computer simulations. Together, these approaches allowed the researchers to map the interactions between the drug molecules and the receptor and to observe directly, at atomic resolution, how cariprazine binds.

The resulting structures revealed which molecular contacts underlie the drug's effects and provided a clearer link between the chemical structure of cariprazine and the response it produces in the receptor.

One of the most striking findings was how sensitive that response can be to apparently minor chemical changes. Altering the drug molecule by as little as a modification involving a single chemical bond could substantially change its effect on the receptor.

The researchers were able to identify structural features that influence whether a compound activates or blocks the receptor, as well as the strength of the response it produces.

That relationship is central to modern drug design. A major challenge for medicinal chemists is to understand how deliberately changing one part of a molecule will alter its biological behaviour. The new results identify structural features of the drug, and specific interactions with the receptor, that may be critical for producing a desired pharmacological response.

A Hungarian drug discovery story comes full circle

The study also marks a new stage in a decades-long Hungarian drug discovery story.

Cariprazine was discovered by researchers at the Hungarian pharmaceutical company Gedeon Richter Plc. It went on to become an established treatment for schizophrenia and bipolar disorder around the world.

The new research was led by Professor György Miklós Keserű, a member of the Hungarian Academy of Sciences, who was also part of the Richter team that originally discovered cariprazine. His involvement connects two very different stages in the life of the same molecule: its original discovery and, decades later, the atomic-level structural explanation of how it acts at one of its principal targets.

‘Following the success of cariprazine, we have now been able to understand at the molecular level how this drug exerts its effects on the dopamine D3 receptor. This represents a breakthrough not only in our understanding of cariprazine's mechanism of action but also provides a new foundation for the design of next-generation psychiatric medicines,’ Keserű said.

Professor László Hunyady, Vice-President for Life Sciences at the Hungarian Academy of Sciences, highlighted the broader link between academic research and pharmaceutical development.

‘These results clearly demonstrate the important role that research in the Hungarian academic sector plays in industrial drug development,’ he said.

The findings were also discussed with Professor Brian Kobilka, a new Honorary Member of the Hungarian Academy of Sciences and a pioneer in the structural biology of membrane receptors.

The dopamine D3 receptor belongs to the large family of G protein-coupled receptors, or GPCRs. Kobilka was awarded the 2012 Nobel Prize in Chemistry for discoveries concerning the structural basis of signalling by this receptor family.

‘This is an exciting discovery that will hopefully inform the development of new medicines for the treatment of complex psychiatric disorders,’ Kobilka said.

From an existing medicine to new molecules

The team did more than explain how an established drug binds to its receptor.

Using the structural information revealed by the study, the researchers designed and validated new compounds that target the dopamine D3 receptor more selectively than previous compounds.

This provides a direct demonstration of how structural biology can feed into drug discovery. By understanding in greater detail how an existing medicine works, researchers can extract design principles and apply them to new molecules.

Greater receptor selectivity could, in the longer term, make it possible to target therapeutically important molecular processes with greater precision. That, in turn, could contribute to treatments with more favourable therapeutic and side-effect profiles, achieving the desired drug effect whilst reducing unwanted effects.

The newly designed compounds are not medicines, however. Further preclinical and clinical studies will be required to establish whether any of them can ultimately be developed for clinical use.

Taken together, the findings provide a detailed structural and pharmacological ‘blueprint’ for designing drug molecules that act on the dopamine D3 receptor. The knowledge could open new avenues for research into treatments for neuropsychiatric conditions.

Structural biology meets medicinal chemistry

The project brought together researchers from the HUN-REN Research Centre for Natural Sciences and international collaborators, including the Weizmann Institute of Science and the University of Nottingham.

By combining structural biology, computational modelling, medicinal chemistry and molecular pharmacology, the team was able to reveal the molecular mechanism by which cariprazine and related compounds act at the dopamine D3 receptor.

The work therefore does two things at once: it provides a more detailed explanation of how a Hungarian-developed medicine used worldwide works, and shows how fundamental research can generate the knowledge needed to design the next generation of drug molecules more rationally.