Glucagon-like peptide-1 (GLP-1) agonists have become a great hit that gains worldwide attention for significant effect for weight loss recently, so are their manufacturers. There should not be much to debate on the anti-obesity effect of GLP-1 agonism, meanwhile targeting the glutamatergic system via N-methyl-D-aspartate (NMDA) receptor antagonism is a relatively new idea in this area. The NMDA receptor plays a critical role in many processes in the brain, in fact there are several NMDA receptor antagonists approved for treating conditions, like depression and Alzheimer’s disease. Given the neurostructural changes and synaptic plasticity brought by blockade of NMDA receptors, it is believed that these mechanisms would mediate body weight homeostasis. A group of Danish and American researchers then confirmed the potential of NMDA receptor agonist MK-801 in reducing food intake and subsequent weight loss in mouse model. In view of unsuitability of MK-801 monotherapy for obesity treatment due to disconcerting adverse effects, they turned to seek safely harnessing the weight-lowering properties of MK-801 by conjugating it to a GLP-1 analogue. The attempt came with a primary success of reduction in body fat mass, plasma cholesterol, blood glucose while eliminating the adverse hyperthermic and hyperlocomotive effects of MK-801. Benchmarking of GLP-1-MK-801 against authority-approved semaglutide further scrutinized the potential of the investigational compound. GLP-1-MK-801 infusion led to a weight loss of 9.5% compared to that of semaglutide infusion, and the weight-lowering effect sustained in subjects with GLP-1-MK-801 but not with semaglutide. This finding could imply a potential of GLP-1-MK-801 conjugate to outperform the current incretin-based treatments. The study demonstrated the potency of GLP-1-MK-801 conjugate treatment in reversing obesity, diabetes, and dyslipidaemia in rodent models of obesity and metabolic disease. In spite of the needs for further investigation of exact mechanism of action and pharmacokinetical engineering for optimization, the discovery from the GLP-1-MK-801 may bring another revolution to the landscape of weight loss therapeutics.

Reference

18. Petersen J, et al. Nature. 2024 May 15. doi: 10.1038/s41586-024-07419-8. Online ahead of print.