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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK091906-01A1
Application #
8243900
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Pawlyk, Aaron
Project Start
2012-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$445,477
Indirect Cost
$147,189
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ericson, Mark D; Singh, Anamika; Tala, Srinivasa R et al. (2018) Human ?-Defensin 1 and ?-Defensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors. J Med Chem 61:3738-3744
Adank, Danielle N; Lunzer, Mary M; Lensing, Cody J et al. (2018) Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice. ACS Chem Neurosci 9:320-327
Tala, Srinivasa R; Singh, Anamika; Lensing, Cody J et al. (2018) 1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization. ACS Chem Neurosci 9:1001-1013
Fleming, Katlyn A; Ericson, Mark D; Freeman, Katie T et al. (2018) Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mic ACS Chem Neurosci 9:1141-1151
Ericson, Mark D; Koerperich, Zoe M; Freeman, Katie T et al. (2018) Arg-Phe-Phe d-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles. ACS Chem Neurosci :
Todorovic, Aleksandar; Lensing, Cody J; Holder, Jerry Ryan et al. (2018) Discovery of Melanocortin Ligands via a Double Simultaneous Substitution Strategy Based on the Ac-His-dPhe-Arg-Trp-NH2 Template. ACS Chem Neurosci 9:2753-2766
Lensing, Cody J; Freeman, Katie T; Schnell, Sathya M et al. (2018) Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over ?-Arrestin 2 Recruitment) Within the Melanocortin Receptors. J Med Chem :
Fleming, Katlyn A; Freeman, Katie T; Ericson, Mark D et al. (2018) Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists. J Med Chem 61:7729-7740
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
Doering, Skye R; Freeman, Katie T; Schnell, Sathya M et al. (2017) Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2. J Med Chem 60:4342-4357

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