Treatment of obesity through NMDA receptor inhibition targeting GLP-1

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

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 reduces food intake and body weight.

NMDA receptor inhibitors such as MK-801 and memantine cause weight loss in rats and reduced intake of palatable food in rodents and nonhuman primates. These antagonists also suppress binge eating in humans.

In this review, researchers developed a new compound MK-801, which combines a small molecular 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 blockade of NMDA receptors, the team created a peptide-based drug combination comprising the NMDA receptor inhibitor MK-801 and a GLP-1 analog.

They used a reducible disulfide bond to engineer redox-sensitive mechanisms to ensure intracellular release of MK-801, allowing for summative cellular GLP-1 agonist and NMDA antagonist activity.

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

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

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

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

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

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

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, increased hyperthermia and hyperlocomotion, making it unsuitable for obesity management.

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

Significant differences in the proteomic and transcriptomic responses of hypothalamic cells associated with synaptic plasticity and glutamatergic transmission indicate that the conjugate can induce 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 disruption of eating habits. The dual effects of NMDA inhibition on food may reduce the weight loss efficacy of systemic exposures to NMDA antagonism.

The significant weight loss potency of the MK-801-GLP-1 conjugate, as well as the robust hypothalamic changes in NMDA receptor neuroplasticity-related proteins and transcripts, suggest that glucagon-like peptide-1-mediated targeting-induced changes in compound biodistribution may effectively bypass MK-801 delivery to vagal afferents and target neuronal cells in the nucleus tractus solitarius (NTS).

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

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

After nine days, the group treated with the MK-801-GLP-1 combination lost 15% of their weight, compared to 3.5% in the original GLP-1 analog 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 metabolic disease mouse models.

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 safe and effective management of obesity. Further studies are required to investigate the weight loss effects of MK-801 in a clinical setting.