Melanin concentrating hormone analogues: contraction of the cyclic structure. 1. Agonist activity
Lebl, M.; Hruby, V.J.; Castrucci, A.M.; Visconti, M.A.; Hadley, M.E.
Journal of Medicinal Chemistry 31(5): 949-954
1988
ISSN/ISBN: 0022-2623 PMID: 3258925 DOI: 10.1021/jm00400a010
Accession: 005874174
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 .alpha.-MSH (.alpha.-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: [Cys7]MCH7-17, [Cys8]MCH8-17, and [Cys10]MCH10-17. 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 1/1,000,000 compared to MCH (1.0) except [Ala5,Cys8]MCH5-17 (0.0008; 1/1250), [Cys10]MCH10-17 (0.00009; 1/10000), and [Cys8]MCH8-17 (0.000001; 1/1000000). In the frog-skin bioassay, [Ala5,Cys10]MCH, although lacking MCH-like activity in the fish-skin bioassay, was equipotent to MCH in its .alpha.-MSH-like components 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.