Highly Selective Cyclic Peptides for Human Melanocortin-4 Receptor (MC-4 R): Design, Synthesis, Bioactive Conformation, and Pharmacological Evaluation as an Anti-Obesity Agent

  • Waleed Danho
  • Joseph Swistok
  • Adrian Cheungv
  • Xin-Jie Chu
  • Yao Wang
  • Li Chen
  • David Bartkovitz
  • Vijay Gore
  • Lida Qi
  • David Fry
  • David Greeley
  • Hongmao Sun
  • Jeanmarie Guenot
  • Lucia Franco
  • Grazyna Kurylko
  • Leonid Rumennik
  • Keith Yagaloff
Part of the American Peptide Symposia book series (APSY, volume 7)

Abstract

Melanocortin (MC) peptides α-, β-, and γ-MSH and adreno-corticotropic hormone (ACTH) are a group of neuropeptides derived from pro-opiomelanocortin hormone (POMC). The physiological actions of these peptides are mediated through five (MCR-1–5) seven-transmembrane G-protein-coupled receptor subtypes. The MSH peptides have been implicated in numerous biological functions [1] including regulation of skin pigmentation, regulation of steroid production, modulation of the immune response, thermo-regulation and obesity [2]. Clarification of the role of melanocortin receptor subtypes, in particular the recently discovered MC-3, MC-4 and MC-5 receptors, has been hampered by the lack of selective peptide ligands. However, recent studies on MCR knockout animals demonstrated that the MC-4 receptor is involved in regulation of feeding. MCR-4 knockout mice display an obesity phenotype that includes maturity onset obesity, hyperglycemia, and hyperinsulinemia. Moreover, it has been reported that a non-selective cyclic MCR-4 peptide agonist (MT II) inhibits food intake when given icv to mice [3]. Consequently, a potent and selective MC-4R agonist is regarded as potentially useful in therapeutic approaches to obesity management. The goal of this work was to identify a selective MCR-4 cyclic peptide agonist for use as a pharmacological tool in obesity and feeding studies and to develop a pharmacophore model applicable to structure-based drug design.

Keywords

Obesity HPLC DMSO Hyperglycemia Clarification 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hruby, V.J., Wilkes, B.C., Cody, W.L, Sawyer, T.K., Hadley, M.E. Pept. Protein Rev. 3, 1–64 (1984).Google Scholar
  2. 2.
    Lu, D., Willard, D., Patel, I.R., Kadwell, S., Overton, L., Kost, T., Luther, M., Chen, W., Yowchik, R.P., Wilkison, W.O., Cone, R.D. Nature 385, 799–802 (1997).CrossRefGoogle Scholar
  3. 3.
    Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., Cone, R. Nature 385, 165–168 (1997).PubMedCrossRefGoogle Scholar
  4. 4.
    Al-Obeidi, F., de L. Castrucci, A.M., Hadley, M.E., Hruby, V.J. J. Med. Chem. 32, 2555–2561 (1998).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • Waleed Danho
    • 1
  • Joseph Swistok
    • 1
  • Adrian Cheungv
    • 1
  • Xin-Jie Chu
    • 1
  • Yao Wang
    • 1
  • Li Chen
    • 1
  • David Bartkovitz
    • 1
  • Vijay Gore
    • 1
  • Lida Qi
    • 1
  • David Fry
    • 1
  • David Greeley
    • 1
  • Hongmao Sun
    • 1
  • Jeanmarie Guenot
    • 1
  • Lucia Franco
    • 1
  • Grazyna Kurylko
    • 1
  • Leonid Rumennik
    • 1
  • Keith Yagaloff
    • 1
  1. 1.Roche Research CenterHoffmann-La Roche Inc.NutleyUSA

Personalised recommendations