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Potential new lead compounds for the treatment of depression and anxiety disorders

Summary: A study identifies potential new drugs that can help treat depression and anxiety disorders without the many adverse effects of other drugs currently being evaluated.

Source: Medical University of Vienna

Currently, various classes of drugs are available for the treatment of mental illnesses, such as depression and anxiety disorders. However, while these drugs confer benefits, they are also associated with unwanted side effects.

Therefore, medical researchers are continuously striving to improve the pharmacological properties of therapeutic agents in order to optimize the benefit/side effect ratio. The research group led by Harald Sitte at the Center for Physiology and Pharmacology at MedUni Vienna conducted a study to identify new drugs that could potentially be used for the treatment of neuropsychiatric disorders.

Importantly, the lead compounds showed a reduced risk of drug abuse and other adverse effects compared to other agents currently under evaluation.

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 of MedUni Vienna, identified the potential of certain substances from the family of synthetic cathinone compounds for the treatment mental illnesses.

Cathinones are derived from cathine, which is found in the khat plant, and are known for their ability to release monoamines such as norepinephrine, dopamine, and serotonin.

“These substances first showed serotonin-related effects in our cellular models, then also in our mouse model”, explains Harald Sitte, referring to this messenger substance considered 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 the attention of scientists due to their preference for releasing serotonin without significantly increasing the level of dopamine in the brain’s “reward center.”

“As a result, the new drugs we are researching are less likely to be abused and are also associated with fewer adverse effects overall,” Harald Sitte points out.

Serotonin release with less risk

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.

The mode of action of these selective serotonin reuptake inhibitors (SSRIs) is based on blocking the reuptake of serotonin from the synaptic cleft (interneuronal space), which increases the amount of serotonin in the interneural space. extracellular.

Mental illnesses such as depression and anxiety disorders can be alleviated by increasing extracellular serotonin levels in the brain. Image is in public domain

Note that “classic” antidepressants inhibit and “block” the serotonin transporter.

In contrast, recent evidence from preclinical and clinical studies has identified the potential of drugs that cause the release of serotonin via the serotonin transporter, i.e. substances that reverse the natural transport direction of the serotonin transporter. serotonin.

However, 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 considered a “party drug” in non-clinical settings.

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

See also

It shows a woman looking depressed

About this psychopharmacology research news

Author: Karin Kirschbichler
Source: Medical University of Vienna
Contact: Karin Kirschbichler – Medical University of Vienna
Image: Image is in public domain

Original research: Free access.
Serotonin releasing agents with reduced off-target effects” by Harald Sitte et al. Molecular psychiatry


Summary

Serotonin releasing agents with reduced off-target effects

Increasing extracellular levels of serotonin (5-HT) in the brain improves symptoms of depression and anxiety-related disorders, for example, social phobias and post-traumatic stress disorder.

Recent evidence from preclinical and clinical studies has established the therapeutic potential of drugs that induce 5-HT release via the 5-HT transporter. Nevertheless, 5-HT releasing compounds currently under clinical investigation carry a risk of abuse and deleterious side effects.

Here we demonstrate that SEnantiomers of certain ring-substituted cathinones show a preference for 5-HT release ex vivo and in vivo, and exert 5-HT-associated effects in preclinical behavioral models.

Importantly, lead cathinone compounds (1) do not induce substantial dopamine release and (2) display reduced off-target activity at vesicular monoamine transporters and 5-HT2B-receptors, indicative of low abuse potential and low potential for adverse effects.

Taken together, our results identify these agents as lead compounds that may prove useful for the treatment of disorders where elevation of 5-HT has been shown to be beneficial.

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