When we think about diseases, we usually focus on their obvious symptoms. A cold can cause a runny nose or stomach issues, while malaria can bring fever and chills. These are called positive symptoms—things that appear because of the illness.
However, diseases can also take things away, such as emotions, social skills, or mental abilities. These are called negative symptoms, and they are much harder to treat.
Schizophrenia is a mental illness that includes both types of symptoms. Positive symptoms include hallucinations, delusions, and disorganized thinking, which current medications can help manage.
However, negative symptoms—such as a lack of emotions or social withdrawal—are not well treated by existing drugs. This is a major challenge because these symptoms make daily life difficult for patients and often lead them to stop taking their medication.
Now, new research from the Warren Center for Neuroscience Drug Discovery (WCNDD) offers hope. Scientists have identified a possible new way to treat both the positive and negative symptoms of schizophrenia.
Their study, published in the Journal of Medicinal Chemistry, was led by Dr. Craig Lindsley at Vanderbilt University, along with researchers from Boehringer Ingelheim, including Daniel Ursu and Henning Priepke.
A New Approach to Treating Schizophrenia
The researchers focused on a part of the brain’s chemical system that involves glutamate, a key neurotransmitter. Glutamate interacts with metabotropic glutamate (mGlu) receptors, which play a role in brain function. Scientists at WCNDD have been studying a special way to target these receptors using positive allosteric modulators (PAMs). Instead of attaching to the main active site of the receptor (like most drugs do), PAMs enhance the receptor’s function by attaching elsewhere. This approach can be more precise and reduce side effects.
The researchers wanted to see if they could develop PAMs that target mGlu1, a specific type of glutamate receptor. Their goal was to create a compound that could improve brain function while avoiding unwanted effects on other similar receptors.
Testing a Promising Compound
The team screened thousands of chemical compounds and optimized their findings to develop a promising new drug-like compound: VU6024578/BI02982816. To test its potential, they conducted several experiments in rodents.
First, they studied its effects on psychosis, one of schizophrenia’s positive symptoms. They used a well-known test where rats and mice were given amphetamine, a drug that causes hyperactivity similar to psychotic episodes in humans.
When they treated these animals with VU6024578/BI02982816, their hyperactivity was reduced in a dose-dependent manner—meaning the effect increased with higher doses of the compound.
Next, they looked at cognition, a negative symptom of schizophrenia. In this test, rats were given MK-801, a drug that impairs their ability to explore new objects. Normally, rats prefer to investigate new objects over familiar ones, but MK-801-treated rats lost this curiosity.
When they were given VU6024578/BI02982816, their natural behavior was restored, suggesting an improvement in cognitive function.
Challenges and Future Research
After seeing success in rodents, the researchers tested the compound in dogs to study how it behaves in larger animals. Unfortunately, the dogs experienced some unexpected side effects, including excessive salivation and muscle stiffness.
These effects disappeared within 24 hours, but they were concerning enough to stop further development of the compound for human use. Interestingly, rats tolerated much higher doses without any noticeable side effects, meaning more research is needed to understand what caused the issues in dogs.
Even though this particular compound will not move forward as a treatment, it is still a valuable research tool. It allows scientists to better study mGlu1 receptors, which could eventually lead to the development of safer drugs that help treat schizophrenia symptoms without harmful side effects.
Why This Research Matters
Schizophrenia remains one of the most challenging mental illnesses to treat, especially when it comes to cognitive impairment and negative symptoms. This research is an important step toward finding a new class of medications that can address these issues.
By continuing to explore mGlu1 and similar receptors, scientists hope to develop new compounds that work in humans without the problems seen in animals. If successful, this could lead to breakthrough treatments that improve both the positive and negative symptoms of schizophrenia, helping patients live more independent and fulfilling lives.
If you care about health, please read studies that scientists find a core feature of depression and this metal in the brain strongly linked to depression.
For more information about health, please see recent studies about drug for mental health that may harm the brain, and results showing this therapy more effective than ketamine in treating severe depression.
The research findings can be found in the Journal of Medicinal Chemistry.
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