Obesity (body mass index, BMI >30) afflicts millions of people in the United States and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. The G-protein coupled melanocortin-3 receptor (MC3R) is expressed in the central nervous system (brain) and is part of the melanocortin pathway involved in the regulation of energy homeostasis. The specific role of the MC3R in the regulation of obesity has not been clearly defined due to a lack of receptor specific ligands and a complex metabolic phenotype of the MC3R knockout mouse. This project is focused upon the drug discovery of MC3R selective molecules (peptide and small molecules), in vitro lead candidate selection, and use of wild type and knockout mice for further molecule lead selection and to probe the role of the MC3R in the novel hypothesis of the MC3R directly involved in the regulation of food intake and satiety. It is anticipated that MC3R ligands have the potential to become therapeutic ligands for obesity related diseases that bypass the human melanocortin-4 receptor (MC4R) agonist associated side effects of male erectile activity and hypertension.

Public Health Relevance

Obesity is a complex disease and is a risk factor for several other associated diseases. The melanocortin pathway has been identified in mice and humans, to regulate obesity. This research project proposes to discover melanocortin-3 receptor (MC3R) selective molecules and study the role of the MC3R in energy homeostasis. These goals are important for target validation and rational design and drug discovery of molecules as potential therapeutic agents regarding obesity, type 2 diabetes and associated diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (56))
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Pawlyk, Aaron
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University of Minnesota Twin Cities
Schools of Pharmacy
United States
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Lensing, Cody J; Adank, Danielle N; Wilber, Stacey L et al. (2017) A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage. ACS Chem Neurosci 8:1262-1278
Ericson, Mark D; Lensing, Cody J; Fleming, Katlyn A et al. (2017) Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. Biochim Biophys Acta 1863:2414-2435
Adank, Danielle N; Lunzer, Mary M; Lensing, Cody J et al. (2017) Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice. ACS Chem Neurosci :
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Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M et al. (2017) A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]?-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands. J Med Chem 60:805-813
Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M et al. (2017) Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at t J Med Chem 60:8103-8114
Lensing, Cody J; Freeman, Katie T; Schnell, Sathya M et al. (2016) An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers. J Med Chem 59:3112-28
Lensing, Cody J; Adank, Danielle N; Doering, Skye R et al. (2016) Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently. ACS Chem Neurosci 7:1283-91
Singh, Anamika; Kast, Johannes; Dirain, Marvin L S et al. (2016) Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors. ACS Chem Neurosci 7:196-205
Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D et al. (2016) Comparative Functional Alanine Positional Scanning of the ?-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors. ACS Chem Neurosci 7:984-94

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