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.
Dizocilpine Maleate , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Obesity , Receptors, N-Methyl-D-Aspartate , Animals , Humans , Male , Mice , Rats , Brain Stem/metabolism , Brain Stem/drug effects , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Dizocilpine Maleate/pharmacology , Dizocilpine Maleate/therapeutic use , Dyslipidemias/drug therapy , Dyslipidemias/metabolism , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Hyperglycemia/drug therapy , Hyperglycemia/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Mice, Inbred C57BL , Neuronal Plasticity/drug effects , Obesity/drug therapy , Obesity/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
