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.
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.
|Singh, Anamika; Dirain, Marvin L; Wilczynski, Andrzej et al. (2014) Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R). ACS Chem Neurosci 5:1020-31|
|Haslach, Erica M; Huang, Huisuo; Dirain, Marvin et al. (2014) Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs). J Med Chem 57:4615-28|
|Singh, Anamika; Dirain, Marvin; Witek, Rachel et al. (2013) Structure-activity relationships of peptides incorporating a bioactive reverse-turn heterocycle at the melanocortin receptors: identification of a 5800-fold mouse melanocortin-3 receptor (mMC3R) selective antagonist/partial agonist versus the mouse melano J Med Chem 56:2747-63|