GLP-1-directed NMDA receptor antagonism for obesity treatment

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  • Mette Q. Ludwig
  • Charlotte Svendsen
  • Eunsang Hwang
  • Amalie W. Kristensen
  • Nicole Fadahunsi
  • Luisa Sachs
  • Rebecca Rohlfs
  • James C. Ford
  • Jonathan D. Douros
  • Brian Finan
  • Bryan Portillo
  • Kyle Grose
  • Annette Feuchtinger
  • Richard D. DiMarchi
  • Kevin W. Williams
  • Anders B. Klein

The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. 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.

Original languageEnglish
Issue number8014
Pages (from-to)1133–1141
Publication statusPublished - 2024

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© The Author(s) 2024.

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