Design, synthesis, and biological evaluation of new cyclic melanotropin peptide analogues selective for the human melanocortin-4 receptor

Jinfa Ying, Xuyuan Gu, Minying Cai, Matthew Dedek, Josef Vagner, Dev B. Trivedi, Victor J. Hruby

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Intensive efforts have been made to develop potent and selective ligands for certain human melanocortin receptors as possible treatments for obesity and sexual dysfunction due to the role of these receptors in feeding behavior, energy homeostasis, sexual function, etc. A number of novel α-MSH analogues were designed and synthesized primarily on the basis of our previous MTII NMR structure. In these peptide analogues, a disulfide or lactam bridge between residues at positions 5 and 8 was used as a conformational constraint to enhance the β-turn spanning His6 and D-Phe7, while the pharmacophore group in Arg8 was mimicked via N α-alkylation of residues 8 or 9 with the guanidinylbutyl group. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues have good binding affinity for the hMC4R (0.7-4.1 nM), but have no binding affinity up to 10 μM at the other three melanocortin receptors. Interestingly, the three hMC4R selective analogues display only 50% binding efficiency, suggesting there is allosteric modulation of the melanocortin-4 receptor. These analogues were found to act as antagonists of the hMC4R. This result represents a discovery of very selective peptide-based antagonists for the hMC4R. The high selectivity may be due to the strong conformational constraint via ring contraction as compared to MTII, and the rigid conformation preferred by these new ligands allows them to recognize only the hMC4R, but not to activate the second messenger. The MTII NMR structure-based design thus not only examined the structural model of melanocortin ligands, but also yielded new biologically unique α-MSH analogues.

Original languageEnglish (US)
Pages (from-to)6888-6896
Number of pages9
JournalJournal of Medicinal Chemistry
Volume49
Issue number23
DOIs
StatePublished - Nov 16 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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