Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2

https://doi.org/10.1016/S0960-894X(03)00412-8Get rights and content

Abstract

The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2 (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, dPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC50 and EC50 below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.

The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2 (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, dPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC50 and EC50 below 10 nM.

  1. Download : Download full-size image

References (25)

  • E.W Roubos

    Comp. Biochem. Physiol., Part A: Mol. Integr. Physiol.

    (1997)
  • D.G Grahame-Smith et al.

    J. Biol. Chem.

    (1967)
  • T.B Ng

    Comp. Biochem. Physiol., B: Comp. Biochem.

    (1990)
  • A Bertolini et al.

    Life Sci.

    (1968)
  • D Huszar et al.

    Cell

    (1997)
  • W Chen et al.

    Cell

    (1997)
  • J.E.S Wikberg

    Eur. J. Pharmacol.

    (1999)
  • R.A Adan et al.

    Eur. J. Pharmacol.

    (2000)
  • M.A Bednarek et al.

    Peptides (New York)

    (1999)
  • M.A Bednarek et al.

    Biochem. Biophys. Res. Commun.

    (1999)
  • P Preville et al.

    Bioorg. Med. Chem. Lett.

    (1997)
  • L.A Carpino et al.

    Tetrahedron Lett.

    (1998)
    H Wenschuh et al.

    Tetrahedron Lett.

    (1996)
  • Cited by (48)

    • MC4R Agonists: Structural Overview on Antiobesity Therapeutics

      2018, Trends in Pharmacological Sciences
      Citation Excerpt :

      In this study, the authors increased agonist’s potency by introducing triazoles and tetrazoles (Figure 5, Structures 1 and 2) [108]. Another very potent non-peptidic structure was reported one year later by Fotsch and co-workers [109], where low-energy structures from NMR data of HFRW were used to identify suitable ring structures. The most potent agonist was then designed, based on a cyclohexane 1,4-diamine decorated with tryptamine to mimic tryptophan, butyl guanidine to resemble arginine, and d-phenylalanine at the first position (Figure 5, Structure 3).

    • 3 Recent Progress Toward Nonpeptide Ligands for the Melanocortin-4 Receptor

      2007, Progress in Medicinal Chemistry
      Citation Excerpt :

      Efforts have been made to directly mimic the pharmacophore of the HFRW motif of melanocortin peptides in order to address the metabolic liability of peptides. [84] The cyclohexane (34) has been designed and synthesized by Fotsch et al. based on the solution structure of the cyclic peptide Ac-Nle-cyclo[Asp-Pro-dPhe-Arg-Trp-Lys]-NH2 determined by NMR [85]. Compound (34) is a potent and selective MC4R agonist (IC50=7.7 nM, EC50=4 nM, IA=93%).

    View all citing articles on Scopus

    Current address: Renovis, 270 Littlefield Avenue, South San Fransico, CA 94080, USA.

    View full text