A novel, bimodal, drug that affects neuroplasticity causes twice the amount of weight loss in obese mice than a GLP-1 agonist alone, researchers have shown. The drug, MK-801, integrates N-methyl-D-aspartate (NMDA) antagonism with glucagon-like peptide-1 (GLP-1) agonism. In mice, it reverses obesity, hyperglycemia and dyslipidemia. The drug’s developers believe that, in humans, it could possibly achieve the same efficacy of current therapeutics with a lower dosage, reducing side effects.
“I consider the drugs available on the market today as the first generation of weight-loss drugs. Now we have developed a new type of weight-loss drug that affects the plasticity of the brain and appears to be highly effective,” said senior author Christoffer Clemmensen, from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen.
The study was published in Nature and the lead author is Jonas Petersen from the Clemmensen Group.
Obesity is a global problem and more than one billion people worldwide have a BMI of 30 or more. Since the launch of GLP-1 agonists (e.g. Ozempic and Wegovy), the weight loss market has been booming and Morgan Stanley Research now expects the market for obesity drugs to reach $77 billion by 2030.
Drugs based on the intestinal hormone GLP-1 effectively target the part of the brain that controls appetite. The NMDA receptor, meanwhile, is a glutamate-activated cation channel. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis.
“The effect of GLP-1 combined with these molecules is very strong. In some cases, the mice lose twice as much weight as mice treated with GLP-1 only,” Clemmensen said. “Our studies in mice show side effects similar to those experienced by patients treated with the weight loss drugs available on the market today, including nausea. But because the drug is so effective, we may be able to lower the dosage and thus mitigate some of the side effects in the future—though we still don’t know how humans respond to the drug.”
He added that, “We already know that GLP-1-based drugs can lead to weight loss. The molecule that we have attached to GLP-1 affects the so-called glutamatergic neurotransmitter system, and in fact, other studies with human participants suggest that this family of compounds has significant weight loss potential. What is interesting here is the effect we get when we combine these two compounds into a single drug,” Clemmensen said.
There is also something distinctly different about MK-801.
“This family of molecules can have a permanent effect on the brain. Studies have demonstrated that even a relatively infrequent treatment can lead to persistent changes to the brain pathologies. We also see molecular signatures of neuroplasticity in our work, but in this case in the context of weight loss,” he added.
“[This drug] exploits GLP-1 as a Trojan Horse to smuggle these small molecules exclusively into the neurons that affect appetite control. Without GLP-1, the molecules that target the NMDA receptor would affect the entire brain and thus be non-specific,” says Petersen.
