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Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA\u00a0receptor-mediated synaptic plasticity are important for body weight homeostasis<jats:sup>1<\/jats:sup>. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.<\/jats:p>","DOI":"10.1038\/s41586-024-07419-8","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T18:02:18Z","timestamp":1715796138000},"page":"1133-1141","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["GLP-1-directed NMDA receptor antagonism for obesity 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