Small-molecule drugs targeting the N-methyl-D-aspartate (NMDA) receptor, a glutamate-activated cation channel broadly expressed in neurons in the brain, had previously been investigated for weight loss in preclinical studies, but were not considered translationally viable due to adverse physiological and behavioural effects. Now, a study in Nature has combined an NMDA receptor antagonist (MK-801) with a glucagon-like peptide 1 (GLP1) analogue to produce potent weight loss without these adverse effects.

The researchers compared the weight loss and metabolic effects of GLP1–MK-801 with the GLP1 analogue alone, MK-801 alone and vehicle controls in diet-induced obese (DIO) mice, and found that GLP1–MK-801 induced significantly greater weight loss than all other conditions over the 14-day treatment period. GLP1–MK-801 also reduced food intake, percentage adipose tissue mass and plasma levels of triglycerides and cholesterol more than the other treatments, including the GLP1 analogue alone. In addition, GLP1–MK-801 produced a greater degree of weight loss than the weight loss drug semaglutide (a GLP1 receptor agonist) in DIO rats, and did not seem to elicit nausea to the same extent as semaglutide.