Potential new lead compounds for the treatment of depression and anxiety

Currently, various types of medications are available to treat mental illnesses such as depression and anxiety
.
However, despite the benefits these drugs bring, they are also associated
with adverse side effects.
Therefore, medical researchers are constantly working to improve the pharmacological properties of therapeutic drugs in order to optimize the efficacy ratio
.
A research team led by Harald Sitter of the Center for Physiology and Pharmacology at the Medical University of Vienna conducted a study to identify new drugs
that could be used to treat neuropsychiatric disorders.
Importantly, lead compounds have shown a lower risk of drug abuse and other adverse effects
compared to other formulations currently being evaluated.
The findings were recently published in the journal Molecular Psychiatry
.

In their preclinical experiments, a research team led by Harald Sitter from the Institute of Pharmacology of the Center for Physiology and Pharmacology at the Medical University of Vienna identified the potential
to synthesize certain substances from the family of cathinone compounds for the treatment of psychiatric disorders.
Cathinones are extracted from cathine, which is found in khat and is known
for its ability to release monoamines such as norepinephrine, dopamine, and serotonin.
Harald Sitter said: "These substances first showed serotonin-related effects in our cell models and then in our mouse models as well
.
" He was referring to this messenger substance, which is considered a key factor
in the medication of depression and anxiety disorders such as social phobia or post-traumatic stress disorder.
The cathinone compounds used in the study attracted the attention of scientists because they tend to release serotonin without significantly increasing dopamine levels
in the brain's "reward centers.
" Harald Sette emphasized: "As a result, the new drugs we are working on are less likely to be abused and are also associated with
fewer adverse effects overall.
"

The risk of serotonin release is small

Psychiatric disorders such as depression and anxiety can be alleviated
by increasing extracellular serotonin levels in the brain.
This is usually achieved through substances that are classified as antidepressants
.
The mode of action of these so-called selective serotonin reuptake inhibitors (SSRIs) is based on blocking serotonin reuptake in the synaptic cleft (neuronal space), which increases the amount of
serotonin in the extracellular space.
It is worth noting that "classical" antidepressants inhibit and "block" the serotonin transporter
.
In contrast, recent evidence from preclinical and clinical studies shows that drugs that induce serotonin release through serotonin transporters (i.
e.
, substances that reverse the natural transport direction of serotonin transporters) have potential
.
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 taken
as a "party drug" in a non-clinical setting.
"Our study identifies the first representatives of a new serotonin-releasing drug that does not produce a variety of side effects
.
" The study was conducted
by first authors Felix Mayer (Florida Atlantic University) and Marco Niello (Center for Physiology and Pharmacology, Vienna Medical University) in collaboration with the Vienna University of Technology, Florida Atlantic University, Peking University and the National Institute on Drug Abuse in Baltimore.

Journal Reference:

1. Felix P.
   Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wan, Marion Holy, Rania Katamish, Walter Sandtner, Yulong Li, Daniela D.
   Pollak, Randy D.
   Blakely, Marko D.
   Mihovilovic, Michael H.
   Baumann, Harald H.
   Sitte.
   Serotonin-releasing agents with reduced off-target effects.
   Molecular Psychiatry, 2022; DOI: 10.
   1038/s41380-022-01843-w