Novel Agouti-Related-Protein-Based Melanocortin-1 Receptor Antagonist

• Published in: Journal of medicinal chemistry 2001-11, Vol.44 (24), p.4114-4124
• Main Authors: Thirumoorthy, Ramanan, Holder, Jerry Ryan, Bauzo, Rayna M, Richards, Nigel G. J, Edison, Arthur S, Haskell-Luevano, Carrie
• Format: Article
• Language: English
• Subjects: Agouti Signaling Protein; Agouti-Related Protein; Amino Acid Sequence; Animals; Biological and medical sciences; Cell Line; Hormones. Endocrine system; Humans; Intercellular Signaling Peptides and Proteins; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Peptide Fragments - chemistry; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Proteins - chemistry; Receptor, Melanocortin, Type 3; Receptors, Corticotropin - agonists; Receptors, Corticotropin - antagonists & inhibitors; Receptors, Melanocortin; Skin - chemistry; Structure-Activity Relationship; Transfection
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010215z

The melanocortin receptors are G-protein coupled receptors (GPCRs) that activate the cAMP signal transduction pathway and are stimulated by the melanocortin agonist α-melanocyte stimulating hormone (α-MSH). Members of these melanocortin receptors are antagonized by agouti (ASP) and agouti-related protein (AGRP), which are the only known endogenous antagonists of GPCRs identified to date. Structure−function studies of the hAGRP(109−118) decapeptide, Tyr-c[Cys-Arg-Phe-Phe-Asn-Ala-Phe-Cys]-Tyr-NH2, by replacing the 26-membered disulfide Cys2-Cys9 ring with lactam bridges resulted in the identification of a novel peripheral skin melanocortin-1 receptor (MC1R) antagonist. This antagonist, Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH2, possesses a 27-membered ring with the lactam bridge being formed from the Cα-carboxyl moiety of Glu (instead of the typical side chain carboxyl moiety) with the amine of the diaminopropionic acid (Dpr) residue. This mouse MC1 receptor antagonist (pA2 = 5.9) is also an antagonist at the brain melanocortin-4 receptor (pA2 = 6.9), with no observable pharmacology at the melanocortin-3 or -5 receptors. This MC1R hAGRP(109−118) based decapeptide is novel in that AGRP(83−132) itself does not bind to, agonize, or antagonize the skin MC1R. Structural analysis has been performed using two-dimensional 1H NMR and computer-assisted molecular modeling (CAMM) techniques in attempts to identify structural features of this Tyr-c[Glu-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH2 (cyclo Glu αCOOH-Dpr βNH) peptide that can differentially result in antagonist versus agonist properties at the mMC1R.