Melanin Concentrating Hormone Analogues: Contraction of the Cyclic Structure. 1. Agonist Activity

Michal Lebl, Victor J. Hruby, Ana M.de L. Castrucci, Maria A. Visconti, Mac E. Hadley

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23 Scopus citations

Abstract

Melanin concentrating hormone (MCH) is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, which is synthesized in the hypothalamus and secreted by the neurohypophysis of teleost fishes. This hormone exhibits both MCH-like as well as α-MSH (α-melanocyte stimulating hormone) like activity. We have examined the role of the disulfide bond for the two contrasting melanotropic activities of MCH. Nine analogues of the parent peptide were synthesized and characterized for biological activity. The disulfide ring was contracted from the 5-14 to the 7-14, 8-14, and 10-14 residues with concomitant substitution of alanine for Cys at position 5 in each of the heptadecapeptides. Similar substitutions were made in a series of MCH5_17 analogues. In addition, the following cyclic peptides also were synthesized: [formula omitted], and [formula omitted]. The fish-skin bioassay is sensitive to MCH at a concentration of 10-12 M. All ring-contracted analogues were inactive at 10-6 M or lower concentrations; less than 1/1000000 compared to MCH (1.0) except [formula omitted]. In the frog-skin bioassay, [Ala5,Cys10] MCH, although lacking MCH-like activity in the fish-skin bioassay, was equipotent to MCH in its α-MSH-like component of activity. Most other analogues were either inactive or much less active than MCH in stimulating melanosome dispersion. These results demonstrate that the disulfide bond between positions 5 and 14 is essential for the MCH-like activity since contraction of the ring generally leads to inactive peptides. Contraction of the disulfide bridge does not, however, have as great an effect on the MSH-like activity of MCH.

Original languageEnglish (US)
Pages (from-to)949-954
Number of pages6
JournalJournal of Medicinal Chemistry
Volume31
Issue number5
DOIs
StatePublished - May 1 1988

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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