Advertisement

The Molecular Pharmacology of Alpha-Melanocyte Stimulating Hormone

Structure—Activity Relationships for Melanotropins at Melanocortin Receptors
  • Victor J. Hruby
  • Guoxia Han
Chapter
Part of the The Receptors book series (REC)

Abstract

α-Melanotropin (α-melanocyte stimulating hormone, α-MSH), Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, is one of the first peptide hormones isolated from the pituitary gland. The biologic functions of α-MSH and structure-activity relationships of α-MSH analogues before 1993 have been extensively researched and reviewed (1–12). This hormone plays a well-known and principal role in pigmentation. Other effects ascribed to this hormone include:
  1. 1.

    Regulation of the release of pituitary and peripheral hormones, such as somatostatin and corticotropin

     
  2. 2.

    Sebotrophic effects, adrenal steroidogenesis, immune response, and cardiovascular and metabolic effects

     
  1. 3.

    Important roles in the nervous system, particularly in the central nervous system (CNS)

     

Keywords

Stimulate Hormone Antagonist Activity Frog Skin Melanocortin Receptor Potent Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Tilders, F. J. H., Swaab, D. F., and van Wimersma Greidanus, T. B. (1977) Melanocyte stimulating hormone: control, chemistry and effects, in Frontiers Hormone Research, Volume 4 (T. B. van Wimersma Greidanus, ed.) S. Karger AG, Basel, New York.Google Scholar
  2. 2.
    Thody, A. J. (1980) The MSH Peptides. Academic Press, New York.Google Scholar
  3. 3.
    Hadley, M. E., Heward, C. B., Hruby, V. J., Sawyer, T. K., and Yang, Y. C. (1981) Biologic actions of melanocyte-stimulating hormone. Ciba Found. Symp. 81, 244–262.PubMedGoogle Scholar
  4. 4.
    Medzihradszky, K. (1982) The bio-organic chemistry of alpha-melanotropin. Med. Res. Rev. 2, 247–270.PubMedCrossRefGoogle Scholar
  5. 5.
    Hruby, V. J., Mosberg, H. I., Sawyer, T. K., Knittel, J. J., Rockway, T. W., Ormberg, J., Darman, P., Chan, W. Y., and Hadley, M. E. (1983) Conformational and dynamic considerations in the design of peptide hormone analogs. Biopolymers 22, 517–530.PubMedCrossRefGoogle Scholar
  6. 6.
    Hruby, V. J., Wilkes, B. C., Cody, W. L., Sawyer, T. K., and Hadley, M. E. (1984) Melanotropins: structural, conformational and biologic considerations in the development of superpotent and superprolonged analogs. Pept. Protein Rev. 3, 1–64.Google Scholar
  7. 7.
    Hadley, M. E. (1988) The Melanotropic Peptides. CRC Press, Boca Raton, FL.Google Scholar
  8. 8.
    Eberle, A. N. (1988) The Melanotropins. Chemistry, Physiology and Mechanisms of Action. S. Karger, Basel, Switzerland.Google Scholar
  9. 9.
    Castrucci, A. M. L., Sawyer, T. K., Al-Obeidi, F., Hruby, V. J., and Hadley, M. E. (1990) Melanotropic peptide antagonists: recent discoveries and biomedical implication. Drugs Future 15, 41–55.Google Scholar
  10. 10.
    Hruby, V. J., Sharma, S. D., Toth, K., Jaw, J. Y., Al-Obeidi, F., Sawyer, T. K., and Hadley, M. E. (1993) Design, synthesis, and conformation of superpotent and prolonged acting melanotropins. Ann. N. Y. Acad. Sci. 680, 51–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Scharrer, B., Smith, E. M., and Stefano, G. B. (1994) Neuropeptides and Immunoregulation. Springer-Verlag, New York.CrossRefGoogle Scholar
  12. 12.
    Hadley, M. E. (1996) The melanotropic hormones, in Endocrinology, Prentice-Hall, Upper Saddle River, NJ, pp. 153–176.Google Scholar
  13. 13.
    Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248–1251.PubMedCrossRefGoogle Scholar
  14. 14.
    Chhajlani, V. and Wikberg, J. E. (1992) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 309, 417–420.PubMedCrossRefGoogle Scholar
  15. 15.
    Chhajlani, V., Muceniece, R., and Wikberg, J. E. (1993) Molecular cloning of a novel human melanocortin receptor. Biochem. Biophys. Res. Commun. 195, 866–873. [published erratum appears in Biochem. Biophys. Res. Commun. 1996 Jan 17; 218: 638].Google Scholar
  16. 16.
    Cone, R. D., Mountjoy, K. G., Robbins, L. S., Nadeau, J. H., Johnson, K. R., RoselliRehfuss, L., and Mortrud, M. T. (1993) Cloning and functional characterization of a family of receptors for the melanotropic peptides. Ann. N.Y. Acad. Sci. 680, 342–363.PubMedCrossRefGoogle Scholar
  17. 17.
    Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson, S. J., DelValle, J., and Yamada, T. (1993) Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246–8250.PubMedGoogle Scholar
  18. 18.
    Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., Delvalle, J., and Yamada, T. (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15174–15179.PubMedGoogle Scholar
  19. 19.
    Gantz, I., Shimoto, Y., Konda, Y., Miwa, H., Dickinson, C. J., and Yamada, T. (1994) Molecular cloning, expression, and characterization of a fifth melanocortin receptor. Biochem. Biophys. Res. Commun. 200, 1214–1220.PubMedCrossRefGoogle Scholar
  20. 20.
    Schioth, H. B., Chhajlani, V., Muceniece, R., Klusa, V., and Wikberg, J. E. (1996) Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci. 59, 797–801.PubMedCrossRefGoogle Scholar
  21. 21.
    Sawyer, T. K., Sanfilippo, P. J., Hruby, V. J., Engel, M. H., Heward, C. B., Burnett, J. B., and Hadley, M. E. (1980) 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biologic activity. Proc. Natl. Acad. Sci. U. S. A. 77, 5754–5758.PubMedCrossRefGoogle Scholar
  22. 22.
    Sawyer, T. K., Hruby, V. J., Darman, P. S., and Hadley, M. E. (1982) [halfCys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: a cyclic alphamelanotropin exhibiting superagonist biologic activity. Proc. Natl. Acad. Sci. U. S. A. 79, 1751–1755.PubMedCrossRefGoogle Scholar
  23. 23.
    Nikiforovich, G. V., Rozenblit, S. A., Shenderovich, M. D., and Chipens, G. I. (1984) Possible bioactive conformations of alpha-melanotropin. FEBS Lett. 170, 315–320.PubMedCrossRefGoogle Scholar
  24. 24.
    Al-Obeidi, F., Hadley, M. E., Pettitt, B. M., and Hruby, V. J. (1989) Design of a new class of superpotent a-melanotropins based on quenched dynamic simulations. J. Am. Chem. Soc. 111, 3413–3416.CrossRefGoogle Scholar
  25. 25.
    Al-Obeidi, F., Castrucci, A. M. L., Hadley, M. E., and Hruby, V. J. (1989) Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J. Med. Chem. 32, 2555–2561.PubMedCrossRefGoogle Scholar
  26. 26.
    Al-Obeidi, F., Hruby, V. J., Yaghoubi, N., Marwan, M. M., and Hadley, M. E. (1992) Synthesis and biologic activities of fatty acid conjugates of a cyclic lactam alpha-melanotropin. J. Med. Chem. 35, 118–123.PubMedCrossRefGoogle Scholar
  27. 27.
    Hadley, M. E., Al-Obeidi, F., Hruby, V. J., Weinrach, J. C., Freedberg, D., Jiang, J. W., and Stover, R. S. (1991) Biologic activities of melanotropic peptide fatty acid conjugates. Pigment Cell Res. 4, 180–185.PubMedCrossRefGoogle Scholar
  28. 28.
    Chaturvedi, D.N., Knittel, J. J., Hruby, V. J., Castrucci, A. M. L., and Hadley, M.E. (1984)Synthesis and biologic actions of highly potent and prolonged acting biotin-labeled melanotropins. J. Med. Chem. 27, 1406–1410.Google Scholar
  29. 29.
    Sugg, E. E., Cody, W. L., Abdel-Malek, Z., Hadley, M. E., and Hruby, V. J. (1986) D-Isomeric replacements within the 6–9 core sequence of Ac-[Nle4]-alpha-MSH4–11-NH,: a topological model for the solution conformation of alpha-melanotropin. Biopolymers 25, 2029–2042.PubMedCrossRefGoogle Scholar
  30. 30.
    Hruby, V. J., Kazmierski, W., Pettitt, B. M., and Al-Obeidi, F. (1988) Conformational constraints in the design of receptor selective peptides: conformational analysis and molecular dynamics, in Molecular Biology of Brain and Endocrine Peptidergic Systems (M. Chretien, M. and McKerns, K. W. eds. ), Plenum, pp. 13–27.Google Scholar
  31. 31.
    Hruby, V. J., Lu, D., Sharma, S.D., Castrucci, A. M. L., Kesterson, R. A., Al-Obeidi F. A., Hadley, M. E., and Cone, R. D. (1995) Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4–10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454–3461.PubMedCrossRefGoogle Scholar
  32. 32.
    Haskell-Luevano, C., Nikiforovich, G., Sharma, S.D., Yang, Y.-Y., Dickinson, C., Hruby, V. J., and Gantz, I. (1997) Biologic and conformational examination of stereochemical modifications using the template melanotropin peptide, Ac-Nlec[Asp-His-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors. J. Med. Chem. 40, 1738–1748.Google Scholar
  33. 33.
    Haskell-Luevano, C., Boteju, L. W., Miwa, H., Dickinson, C., Gantz, I., Yamada, T., Hadley, M. E., and Hruby, V. J. (1995) Topographical modification of melanotropin peptide analogues with beta-methyltryptophan isomers at position 9 leads to differential potencies and prolonged biologic activities. J. Med. Chem. 38, 4720–4729.Google Scholar
  34. 34.
    Sawyer, T. K., Staples, D. J., Castrucci, A. M. L., and Hadley, M. E. (1989) Discovery and structure-activity relationships of novel alpha-melanocyte-stimulating hormone inhibitors. Pept. Res. 2, 140–146.PubMedGoogle Scholar
  35. 35.
    Al-Obeidi, F., Hruby, V. J., Hadley, M. E., Sawyer, T. K., and Castrucci, A. M. L. (1990) Design, synthesis, and biologic activities of a potent and selective alphamelanotropin antagonist. Int. J. Pept. Protein Res. 35, 228–234.PubMedCrossRefGoogle Scholar
  36. 36.
    Sawyer, T. K., Staples, D. J., Castrucci, A. M. L., Hadley, M. E., Al-Obeidi, F. A., Cody, W. L., and Hruby, V. J. (1990) Alpha-melanocyte stimulating hormone message and inhibitory sequences: comparative structure-activity studies on melanocytes. Peptides 11, 351–357.PubMedCrossRefGoogle Scholar
  37. 37.
    McCormack, A. M., Carter, R. J., Thody, A. J., and Shuster, S. (1982) Des-acetyl MSH and gamma-MSH act as partial agonists to alpha-MSH on the Anolis melanophore. Peptides 3, 13–16.PubMedCrossRefGoogle Scholar
  38. 38.
    Yajima, H. and Kubo, K. (1965) Studies on peptides. II. Synthesis and physiological properties of n-histidyl-D-phenylalanyl-D-arginyl-n-tryptophanylglycine, an optical antipode of an active fragment of a-melanocyte-stimulating hormone. J. Am. Chem. Soc. 87, 2039–2044.PubMedCrossRefGoogle Scholar
  39. 39.
    Yajima, H., Kawasaki, K., Okada, Y., and Lande, S. (1965) Studies on peptides. V. Color-lightening action of histidylphenylalanylarginyl-5-methoxytryptamine on frog skin in vitro. Biochem. Biophys. Acta 107, 141–143.PubMedCrossRefGoogle Scholar
  40. 40.
    Yajima, H. and Kawasaki, K. (1968) Studies on peptides. XVII. Synthesis of N-alpha-acetyl-seryl-tyrosyl-seryl-methionyl-glutamyl-histidyl-phenylalanyl-arginyl)-5-methoxy-tryptamine and its physiological properties on the frog melanocyte in vitro. Chem. Pharm. Bull. (Tokyo) 16, 1379–1382.CrossRefGoogle Scholar
  41. 41.
    Castrucci, A. M. L., Sherbrooke, W. C., Sawyer, T. K., Staples, D. J., Tuma, M. C. B., and Hadley, M. E. (1994) Discovery of an alpha-melanotropin antagonist effective in vitro. Peptides 15, 627–632.PubMedCrossRefGoogle Scholar
  42. 42.
    Castrucci, A. M. L., Hadley, M. E., Sawyer, T. K., Wilkes, B. C., Al-Obeidi, F., Staples, D. J., de Vaux, A. E., Dym, O., Hintz, M. F., Riehm, J. P., Rao, K. R., and Hruby, V. J. (1989) alpha-Melanotropin: the minimal active sequence in the lizard skin bioassay. Gen. Comp. Endocrinol. 73, 157–163.Google Scholar
  43. 43.
    Sawyer, T. K., Staples, D. J., Castrucci, A. M. L., Hadley, M. E., Al-Obeidi, F. A., Cody, W. L., and Hruby, V. J. (1990) alpha-Melanocyte stimulating hormone message and inhibitory sequences: comparative structure-activity studies on melanocytes. Peptides 11, 351–357.Google Scholar
  44. 44.
    Adan, R. A., Oosterom, J., Ludvigsdottir, G., Brakkee, J. H., Burbach, J. P., and Gispen, W.H. (1994) Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. Eur. J. Pharmacol. 269, 331–337.PubMedCrossRefGoogle Scholar
  45. 45.
    Quillan, J. M., Jayawickreme, C. K., and Lerner, M. R. (1995) Combinatorial diffusion assay used to identify topically active melanocyte-stimulating hormone receptor antagonists. Proc. Natl. Acad. Sci. U. S. A. 92, 2894–2898.PubMedCrossRefGoogle Scholar
  46. 46.
    Jayawickreme, C. K., Quillan, J. M., Graminski, G. F., and Lerner, M. R. (1994) Discovery and structure-function analysis of alpha-melanocyte-stimulating hormone antagonists. J. Biol. Chem. 269, 29846–29854.PubMedGoogle Scholar
  47. 47.
    Haskell-Luevano, C., Miwa, H., Dickinson, C., Hruby, V. J., Yamada, T., and Gantz, I. (1994) Binding and cAMP studies of melanotropin peptides with the cloned human peripheral melanocortin receptor, hMC1-R. Biochem. Biophys. Res. Commun. 204, 1137–1142.PubMedCrossRefGoogle Scholar
  48. 48.
    Schioth, H. B., Muceniece, R., Wikberg, J. E., and Chhajlani, V. (1995) Characterisation of melanocortin receptor subtypes by radioligand binding analysis. Eur. J. Pharmacol. 288, 311–317.PubMedCrossRefGoogle Scholar
  49. 49.
    Haskell-Luevano, C., Miwa, H., Dickinson, C., Hadley, M. E., Hruby, V. J., Yamada, T., and Gantz, I. (1996) Characterizations of the unusual dissociation properties of melanotropin peptides from the melanocortin receptor, hMC 1-R. J. Med. Chem. 39, 432–435.PubMedCrossRefGoogle Scholar
  50. 50.
    Schioth, H. B., Muceniece, R., and Wikberg, J. E. (1996) Characterisation of the melanocortin 4 receptor by radioligand binding. Pharmacol. Toxicol. 79, 161–165.PubMedCrossRefGoogle Scholar
  51. 51.
    Adan, R. A., Cone, R. D., Burbach, J. P., and Gispen, W. H. (1994) Differential effects of melanocortin peptides on neural melanocortin receptors. Mol. Pharmacol. 46, 1182–1190.PubMedGoogle Scholar
  52. 52.
    Hadley, M. E., Anderson, B., Heward, C. B., Sawyer, T. K., and Hruby, V. J. (1981) Calcium-dependent prolonged effects on melanophores of [4-norleucine, 7-n-phenylalanine]-alpha-melanotropin. Science 213, 1025–1027.PubMedCrossRefGoogle Scholar
  53. 53.
    Hadley, M. E., Hruby, V. J., Jiang, J., Sharma, S. D., Fink, J. L., Haskell-Luevano, C., Bentley, D. L., Al-Obeidi, F., and Sawyer, T. K. (1996) Melanocortin receptors: identification and characterization by melanotropic peptide agonists and antagonists. Pigment Cell Res. 9, 213–234.PubMedCrossRefGoogle Scholar
  54. 54.
    Sharma, S. D., Jiang, J., Hadley, M. E., Bentley, D. L., and Hruby, V. J. (1996) Melanotropic peptide-conjugated beads for microscopic visualization and characterization of melanoma melanotropin receptors. Proc. Natl. Acad. Sci. U. S. A. 93, 13715–13720.PubMedCrossRefGoogle Scholar
  55. 55.
    Li, S. J., Varga, K., Archer, P., Hruby, V. J., Sharma, S. D., Kesterson, R. A., Cone, R. D., and Kunos, G. (1996) Melanocortin antagonists define two distinct pathways of cardiovascular control by alpha-and gamma-melanocyte-stimulating hormones. J. Neurosci. 16, 5182–5188.PubMedGoogle Scholar
  56. 56.
    Schwyzer, R. (1977) ACTH: a short introductory review. Ann. N. Y. Acad. Sci. 297, 3–26.PubMedCrossRefGoogle Scholar
  57. 57.
    Kastin, A. J., Zadina, J. E., Olson, R. D., and Banks, W. A. (1996) The history of neuropeptide research: version 5.a. Ann. N. Y. Acad. Sci. 780, 1–18.PubMedCrossRefGoogle Scholar
  58. 58.
    Wessells, H., Fuciarelli, K., Hansen, J., Hadley, M. E., Hruby, V. J., Dorr, R., and Levine, N. (1998) Synthetic melanotropic peptide initiates erections in men with psycogenic erectile dysfunction: double-blind, placebo controlled crossover study. J. Urology 160, 389–393.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Victor J. Hruby
  • Guoxia Han

There are no affiliations available

Personalised recommendations