The melanocortin receptors (MCRs) are G-Protein Coupled Receptors (GPCRs) that modulate and control many critical physiological processes in animals including pigmentation, response to stress, feeding behavior, energy balance, sexual function and behavior, inflammatory response, cardiovascular function, immune response, pain and others. They also are involved in many of our most common degenerative diseases including adrenal dysfunction, obesity, anorexia, pigmentary disorders, sexual dysfunction, prolonged and neuropathic pain, inflammatory disorders, cardiovascular disease and others. Yet there are few compounds that have been developed and are pharmaceuticals in use for treatment of these diseases which are our most common and difficult to treat diseases. This grant is dedicated to developing more potent, receptor selective, and specific and most efficacious ligands for the melancortin 1(MCI), melanocortin 3 (MC3), melanocortin 4 (MC4), and melanocortin 5 (MC5) receptors. These novel ligands, which are biological stable and available for in vivo applications, will be useful for studying the pharmacology, physiology and medical applications of melanotropin ligands.
The specific aims we will pursue include: 1) development and use of novel protein/peptide topologies and scaffolds, in conjunction with novel constrained amino acids, to design and synthesize novel orthosteric, allosteric, and biased melanotropin peptides and peptide mimetics with enhanced stability, bioavailability, selectivity and potency for the melanocortin receptors;2a) to examine binding affinities, cyclic AMP production, efficacies, Ca+2 assays and assays for -arrestin. The novel ligands for the hMC1R, hMC3R, hMC4R and hMC5R receptors will be examined with special attention to the development of biased ligands;and 2b) use of novel selective ligands, especially those with biased activity, to explore novel physiological functions that can lead to novel drugs with our collaborators.

Public Health Relevance

The melanotropin peptides and melanocortin receptors are primordial peptides and G-protein coupled receptors that affect many critical biological functions and which are involved in many critical aspects of human health and disease including pigmentary disorders, obesity, prolonged and neuropathic pain, diabetes, cancer, sexual response and motivation, inflammatory response, and many others. We are world leaders in developing selective agonists and antagonists for melanocortin receptors and we will utilize our knowledge and expertise to develop new ligands for these receptors that are more biologically specific and bioavailable so that potential drugs will emerge from these investigations.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-R (04))
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Dunsmore, Sarah
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University of Arizona
Schools of Arts and Sciences
United States
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Rinne, Petteri; Rami, Martina; Nuutinen, Salla et al. (2017) Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages. Circulation 136:83-97
Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake et al. (2017) Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56:4201-4209
Cai, Minying; Hruby, Victor J (2016) Design of cyclized selective melanotropins. Biopolymers 106:876-883
Hruby, Victor J (2016) Design of cyclic peptides with biological activities from biologically active peptides: the case of peptide modulators of melanocortin receptors. Biopolymers 106:884-888
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Cai, Minying; Marelli, Udaya Kiran; Bao, Jennifer et al. (2015) Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors. J Med Chem 58:6359-67
Carotenuto, Alfonso; Merlino, Francesco; Cai, Minying et al. (2015) Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor. J Med Chem 58:9773-8
Van der Poorten, Olivier; Fehér, Krisztina; Buysse, Koen et al. (2015) Azepinone-Containing Tetrapeptide Analogues of Melanotropin Lead to Selective hMC4R Agonists and hMC5R Antagonist. ACS Med Chem Lett 6:192-7

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