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GLP-1 and NMDA-targeted weight loss drugs show promise

Summary: Researchers have developed a new weight-loss drug that combines GLP-1 with molecules targeting NMDA receptors in the brain. This “Trojan horse” approach allows the drug to specifically target the appetite control center, leading to significant weight loss in mice. The drug shows promise in the fight against obesity by potentially offering a more effective treatment with lower doses and fewer side effects.

Highlights:

  • A new weight loss drug combines GLP-1 and NMDA receptor blockers.
  • The drug specifically targets the appetite control center of the brain.
  • In mice, the drug caused significant weight loss and reduced side effects.

Source: University of Copenhagen

In a study published in Nature, Christoffer Clemmensen and colleagues demonstrate a new use of the weight loss hormone GLP-1. GLP-1 can be used as a “Trojan horse” to smuggle a specific molecule into the brains of mice, where it successfully affects brain plasticity and causes weight loss.

“I consider the drugs available on the market today to be the first generation of weight loss drugs. We have now developed a new type of weight-loss drug that affects brain plasticity and appears to be very effective,” says Clemmensen, of the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and lead author of the study. study.

It shows a woman and a measuring tape.
Additionally, the new drug could provide an alternative for those who do not respond well to existing weight loss medications. Credit: Neuroscience News

“The effect of GLP-1 combined with these molecules is very strong. In some cases, mice lost twice as much weight as mice treated with GLP-1 alone.

This means that future patients will potentially be able to achieve the same effect with a lower dose. Additionally, the new drug could provide an alternative for those who do not respond well to existing weight loss medications.

“Our studies in mice show side effects similar to those experienced by patients treated with weight loss drugs available on the market today, including nausea. But because the drug is very effective, we may be able to reduce the dose and thus alleviate some side effects in the future, although we still do not know how humans react to the drug,” explains Clemmensen.

Tests of the new weight loss drug are still in the so-called preclinical phase, which is based on studies on cells and laboratory animals. The next step is clinical trials with human participants.

“We already know that GLP-1 drugs can cause weight loss. The molecule we attached to GLP-1 affects the glutamatergic neurotransmitter system, and in fact, other studies with human participants suggest that this family of compounds has significant weight loss potential.

“What’s interesting here is the effect we get when we combine these two compounds into one drug,” says Clemmensen.

The drug must undergo three phases of clinical trials on human participants. According to Clemmensen, it may therefore take eight years before the drug can be available on the market.

The brain defends excessive body weight

Clemmensen and his colleagues developed an interest in molecules used to treat chronic depression and Alzheimer’s disease.

The molecules block a receptor protein called the NMDA receptor, which plays a key role in long-term changes in brain connections and has received scientific attention in the areas of learning and memory. Drugs targeting these receptors will strengthen and/or weaken specific nerve connections.

“This family of molecules can have a permanent effect on the brain. Studies have shown that even relatively infrequent treatment can lead to persistent changes in brain pathologies. We also see molecular signatures of neuroplasticity in our work, but here in the context of weight loss,” he explains.

The human body evolved to protect a certain body weight and body fat. From an evolutionary perspective, this has probably been to our advantage, because it means we have been able to survive periods of food scarcity. Today, food shortage is no longer a problem in much of the world, where a growing share of the population suffers from obesity.

“Today, more than a billion people worldwide have a BMI of 30 or more. It is therefore increasingly relevant to develop drugs to combat this disease and which can help the body maintain a lower weight. This topic is one that we invest a lot of energy into researching,” says Clemmensen.

A Trojan horse smuggles small molecules that modulate neuroplasticity into appetite-regulating neurons

We know that medications based on the gut hormone GLP-1 effectively target the part of the brain critical for weight loss, namely the appetite control center.

“What is spectacular, at the cellular level, in this new drug is the fact that it combines GLP-1 and molecules that block the NMDA receptor. It exploits GLP-1 as a Trojan horse to smuggle these small molecules exclusively into neurons that affect appetite control.

“Without GLP-1, molecules that target the NMDA receptor would affect the entire brain and therefore be nonspecific,” explains postdoc Jonas Petersen of the Clemmensen group, first author of the study and chemist who synthesized the molecules. .

Nonspecific drugs are often associated with serious side effects, which have been previously observed with drugs intended for the treatment of different neurobiological conditions.

“Many brain disorders are difficult to treat because medications must cross the blood-brain barrier. While large molecules like peptides and proteins generally have difficulty accessing the brain, many small molecules have unrestricted access to the entire brain.

“We used the specific access of the GLP-1 peptide to the appetite control center in the brain to deliver one of these otherwise non-specific substances to that region only,” explains Clemmensen.

“In this study we focused on obesity and weight loss, but this is actually a completely new approach to delivering drugs to specific parts of the brain. So I hope that our research can pave the way for a whole new class of drugs to treat diseases such as neurodegenerative diseases or psychiatric disorders.

Clemmensen, together with postdoc Jonas Petersen and a former University of Copenhagen scientist (Anders Klein), co-founded the biotechnology company Ousia Pharma, which is a spin-off company from the University of Copenhagen. The company continues to develop the medical concept presented in this study for the treatment of severe obesity.

About this neuropharmacology research news

Author: Christoffer Clemmensen
Source: University of Copenhagen
Contact: Christoffer Clemmensen – University of Copenhagen
Picture: Image is credited to Neuroscience News

Original research: Free access.
“GLP-1-directed NMDA receptor antagonism for the treatment of obesity” by Christoffer Clemmensen et al. Nature


Abstract

GLP-1-directed NMDA receptor antagonism for the treatment of obesity

THE NOTThe -methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is essential for many brain processes. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis.

Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, Hyperglycemia and dyslipidemia in rodent models of metabolic diseases.

GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting MK-801 to brain regions expressing the GLP-1 receptor avoids adverse physiological and behavioral effects associated with MK-801 monotherapy.

In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular agonism of mixed GLP-1 receptors and NMDA receptor antagonism for safe and effective treatment of obesity.

News Source : neurosciencenews.com
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