Stereochemical Studies of the Monocyclic Agouti-Related Protein (103−122) Arg-Phe-Phe Residues:  Conversion of a Melanocortin-4 Receptor Antagonist into an Agonist and Results in the Discovery of a Potent and Selective Melanocortin-1 Agonist

• Published in: Journal of medicinal chemistry Vol. 47; no. 27; pp. 6702 - 6710
• Main Authors: Joseph, Christine G, Wang, Xiang S, Scott, Joseph W, Bauzo, Rayna M, Xiang, Zhimin, Richards, Nigel G, Haskell-Luevano, Carrie
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 30.12.2004
• Subjects: Agouti-Related Protein; Amino Acid Sequence; Animals; Biological and medical sciences; Cells, Cultured; Humans; Intercellular Signaling Peptides and Proteins; Medical sciences; Mice; Miscellaneous; Models, Molecular; Molecular Sequence Data; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Conformation; Proteins - chemistry; Receptor, Melanocortin, Type 1 - agonists; Receptor, Melanocortin, Type 4 - agonists; Receptor, Melanocortin, Type 4 - antagonists & inhibitors; Agonist; Cyclic peptides; Agouti related protein; Homology; Selectivity; In vitro; Modeling; Structure activity relation; MC4 melanocortin receptor; Peptide fragment; Disulfide bond; Sulfur peptide; Molecular model; Peptidergic receptor; Peptide synthesis; Solid phase; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0492756

The agouti-related protein (AGRP) is an endogenous antagonist of the centrally expressed melanocortin receptors. The melanocortin-4 receptor (MC4R) is involved in energy homeostasis, food intake, sexual function, and obesity. The endogenous hAGRP protein is 132 amino acids in length, possesses five disulfide bridges at the C-terminus of the molecule, and is expressed in the hypothalamus of the brain. We have previously reported that a monocyclic hAGRP(103−122) peptide is an antagonist at the melanocortin receptors expressed in the brain. Stereochemical inversion from the endogenous l- to d-isomers of single or multiple amino acid modifications in this monocyclic truncated hAGRP sequence resulted in molecules that are converted from melanocortin receptor antagonists into melanocortin receptor agonists. The Asp-Pro-Ala-Ala-Thr-Ala-Tyr-cyclo[Cys-Arg-DPhe-DPhe-Asn-Ala-Phe-Cys]-Tyr-Ala-Arg-Lys-Leu peptide resulted in a 60 nM melanocortin-1 receptor agonist that is 100-fold selective versus the mMC4R, 1000-fold selective versus the mMC3R, and ca. 180-fold selective versus the mMC5R. In attempts to identify putative ligand−receptor interactions that may be participating in the agonist induced stimulation of the MC4R, selected ligands were docked into a homology molecular model of the mMC4R. These modeling studies have putatively identified hAGRP ligand DArg111-mMC4RAsn115 (TM3) and the hAGRP DPhe113-mMC4RPhe176 (TM4) interactions as important for agonist activity.