title: Novel agouti-related-protein-based melanocortin-1 receptor antagonist.
abstract: The melanocortin receptors are G-protein coupled receptors (GPCRs) that activate the cAMP signal transduction pathway and are stimulated by the melanocortin agonist alpha-melanocyte stimulating hormone (alpha-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-NH(2), by replacing the 26-membered disulfide Cys(2)-Cys(9) 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-NH(2), possesses a 27-membered ring with the lactam bridge being formed from the Calpha-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 (pA(2) = 5.9) is also an antagonist at the brain melanocortin-4 receptor (pA(2) = 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 (1)H 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-NH(2) (cyclo Glu alphaCOOH-Dpr betaNH) peptide that can differentially result in antagonist versus agonist properties at the mMC1R.
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: R
authors.initials: R
authors.lastname: Thirumoorthy
authors.forename: J R
authors.initials: JR
authors.lastname: Holder
authors.forename: R M
authors.initials: RM
authors.lastname: Bauzo
authors.forename: N G
authors.initials: NG
authors.lastname: Richards
authors.forename: A S
authors.initials: AS
authors.lastname: Edison
authors.forename: C
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry*; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors*; D044101:Receptors, Melanocortin; D012867:Skin / Q000737:chemistry; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C515198:AGRP protein, human; D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007769:Lactams; C470053:Mc3r protein, mouse; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011506:Proteins; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C440615:tyrosyl-cyclo(glutamyl-arginyl-phenylalanyl-phenylalanyl-aspargyl-alanyl-phenylalanyl-diaminopropionyl)-tyrosinamide