Novel agouti-related-protein-based melanocortin-1 receptor antagonist

J Med Chem. 2001 Nov 22;44(24):4114-24. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agouti Signaling Protein
  • Agouti-Related Protein
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Proteins / chemistry*
  • Receptor, Melanocortin, Type 3*
  • Receptors, Corticotropin / agonists
  • Receptors, Corticotropin / antagonists & inhibitors*
  • Receptors, Melanocortin
  • Skin / chemistry
  • Structure-Activity Relationship
  • Transfection


  • AGRP protein, human
  • Agouti Signaling Protein
  • Agouti-Related Protein
  • Agrp protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Lactams
  • Mc3r protein, mouse
  • Peptide Fragments
  • Peptides, Cyclic
  • Proteins
  • Receptor, Melanocortin, Type 3
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • tyrosyl-cyclo(glutamyl-arginyl-phenylalanyl-phenylalanyl-aspargyl-alanyl-phenylalanyl-diaminopropionyl)-tyrosinamide