Treatment of obesity through NMDA receptor inhibition targeting GLP-1

In a recent study published in Nature, researchers developed a new bimodal drug, MK-801, that successfully treats obesity, hyperglycemia, and dyslipidemia in mouse models of metabolic diseases by combining N-methyl-D-aspartate (NMDA) receptor antagonism with glucagon-like peptide-1 receptor antagonism (GLP-1).

The NMDA receptor is an important brain ion channel that influences body weight homeostasis. Obesity is associated with glutamatergic neurotransmission and synaptic plasticity mediated by NMDA receptors.

In mice, inhibition of NMDA receptor function in the brainstem increases short-term food intake, but antagonism of these receptors in the hypothalamus decreases food intake and body weight.

NMDA receptor inhibitors such as MK-801 and memantine result in reduced weight gain in rats and reduced intake of palatable foods in rodents and non-human primates. These antagonists also suppress binge eating in humans.

In this review, researchers developed a new compound, MK-801, which combines a small-molecule antagonist with a peptide agonist for the treatment of obesity.

MK-801 delivers a small molecule ionotropic receptor modifier targeting the G protein-coupled receptor. To avoid problems associated with non-specific blocking of NMDA receptors, the team created a combination of peptide-based drugs, including the NMDA receptor inhibitor MK-801 and a GLP-1 analogue.

They used a reducible disulfide bond to engineer redox-sensitive mechanisms to mediate intracellular release of MK-801, allowing for additive cellular activity of GLP-1 agonists and NMDA antagonists.

The researchers developed MK-801 by cleaving and purifying peptides after producing a disulfide linker and assessing the compound's ability to transmit protraction. They functionalized the disulfide linker after reacting with an amine-containing drug.

They were evaluated in vitro using reversed-phase ultra-performance liquid chromatography (UPLC) and bioluminescent resonance energy transfer (BRET) assays.

Conjugates containing various peptide analogs have also been created, including peptide YY (PYY), glucose insulinotropic peptide (GIP), and a GIP/GLP-1 coagonist. These conjugates may increase the effectiveness of weight loss.

Researchers examined the glucometabolic characteristics of MK-801 in the diabetic db/db mouse model and double male Sprague-Dawley (SD) rats. They studied the adverse profile of MK-801-GLP-1, especially its effects on hyperthermia and hyperlocomotion.

They performed metabolic phenotyping and indirect calorimetry studies using DIO C57BL/6J mice. After determining the dosage, they assessed the metabolic effects in vivo, comparing MK-801-GLP-1 with MK-801 therapy and vehicles.

The team confirmed the effectiveness of MK-801-GLP-1 in managing energy balance by normalizing body weight and fat mass compared to age-matched control groups.

They conducted comparative transcriptomic studies to determine the effects of the conjugate on the brainstem and mesolimbic reward system. The significant difference in weight loss between the two treatments may complicate the interpretation of changes in transcriptional regulation.

Daily subcutaneous injections of MK-801 resulted in dose-dependent reductions in food intake and body weight. Chronic therapy, on the other hand, increases hyperthermia and hyperlocomotion, making it unsuitable for the management of obesity.

In various rodent models of metabolic disease and obesity, treatment with the MK-801-GLP-1 combination significantly corrected obesity, diabetes, and dyslipidemia.

Significant differences in proteomic and transcriptomic responses of hypothalamic cells associated with synaptic plasticity and glutamatergic transmission indicate that the conjugate may cause neurostructural changes in neurons expressing glucagon-like peptide-1.

The weight loss benefits of MK-801 may be due to a combination of effects on energy balance and disrupted eating habits. The bidirectional effects of dietary NMDA inhibition may reduce the weight loss efficacy of systemic exposure to NMDA antagonism.

The significant weight loss efficacy of the MK-801-GLP-1 conjugate, as well as strong hypothalamic changes in proteins and transcripts associated with NMDA receptor neuroplasticity, indicate that changes in the biodistribution of the compound caused by glucagon-like peptide-1-regulated targeting, can effectively bypass delivery of MK-801 to vagal afferents and target neuronal cells in the nucleus tractus solitaria (NTS).

MK-801-GLP-1 reduced body weight synergistically in mice, resulting in a 23% weight reduction v/v compared with dosed monotherapies.

In DIO mice, a single injection of GLP-1 or MK-801-GLP-1 reduced blood glucose levels, but equimolar treatment with MK-801 had no significant effect on glycemia.

After nine days, the group treated with the MK-801-GLP-1 combination had lost 15% of their weight, compared to 3.5% in the original GLP-1 analogue group.

The study showed that a bimodal molecular strategy combining NMDA receptor antagonism and glucagon-like peptide-1 receptor antagonism could successfully correct obesity, hyperglycemia, and dyslipidemia in mouse models of metabolic diseases.

This method demonstrates the viability of using peptide-regulated targeting to create cell-specific modulation of ionotropic receptors and the therapeutic potential of unimolecular combined glucagon-like peptide-1 receptor agonism and NMDA receptor antagonism for the safe and effective management of obesity. Further studies are required to examine the weight-loss effects of MK-801 in a clinical setting.