Researchers identify potential lead substances for the treatment of neuropsychiatric diseases

Researchers identify potential lead substances for the treatment of neuropsychiatric diseases

There are currently different classes of medications available to treat mental illnesses – such as depression and anxiety disorders. However, although these medications offer benefits, they are also associated with unwanted side effects. Consequently, medical researchers continually strive to improve the pharmacological properties of therapeutics to optimize the benefit-to-side effect ratio.

Harald Sitte's research group at the Center for Physiology and Pharmacology at MedUni Vienna conducted a study to identify new drugs that could potentially be used to treat neuropsychiatric diseases. Importantly, the lead compounds had a lower risk of drug abuse and other side effects compared to other agents currently being studied. The research results were recently published in the journal Molecular Psychiatry.

In their preclinical experiments, the research team led by Harald Sitte from the Institute of Pharmacology of the Center for Physiology and Pharmacology at MedUni Vienna identified the potential of certain substances from the family of synthetic cathinone compounds for the treatment of mental illnesses. Cathinones are derived from cathine found in the khat plant and are known for their ability to release monoamines such as norepinephrine, dopamine and serotonin.

“These substances initially showed serotonin-like effects in our cell models and then also in our mouse model,” says Harald Sitte, referring to this messenger substance, which is a key factor in the drug treatment of depression and anxiety disorders such as social phobias or post-traumatic stress disorder. The cathinone compounds used in the study caught scientists' attention because of their preference for releasing serotonin without significantly increasing dopamine levels in the brain's "reward center."

As a result, the new drugs we are researching are less likely to be misused and are associated with fewer overall side effects.”

Harald Sitte, Institute of Pharmacology at the Center for Physiology and Pharmacology at MedUni Vienna

Serotonin release with less risk

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Mental illnesses such as depression and anxiety disorders can be alleviated by increasing extracellular serotonin levels in the brain. This is usually achieved by substances classified as antidepressants. These so-called selective serotonin reuptake inhibitors (SSRIs) work by blocking the reuptake of serotonin from the synaptic cleft (neuronal space), thereby increasing the amount of serotonin in the extracellular space. Remarkably, “classic” antidepressants inhibit and “block” the serotonin transporter. In contrast, recent evidence from preclinical and clinical studies identified the potential of drugs that elicit the release of serotonin via the serotonin transporter, that is, substances that reverse the natural direction of transport of the serotonin transporter. However, the serotonin-releasing agents currently in clinical trials carry the risk of abuse and harmful side effects–such as MDMA, also known as “ecstasy,” which is used as a “party drug” in non-clinical settings.

“Our research has identified the first representatives of a new serotonin-releasing class of drugs that do not cause various side effects,” says study leader Harald Sitte, summarizing the results of the study, which was carried out by first author Felix Mayer (Florida Atlantic University) and Marco Niello (Center for Physiology and Pharmacology at MedUni Vienna) in collaboration with the Vienna University of Technology, Florida Atlantic University Peking University and the National Institute of Drug Abuse in Baltimore.

Source:

Medical University of Vienna

Reference:

Mayer, FP, et al. (2022) Serotonin-releasing agents with reduced off-target effects. Molecular Psychiatry. doi.org/10.1038/s41380-022-01843-w.

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