Letters in Peptide Science

, Volume 5, Issue 5–6, pp 337–340 | Cite as

The relationship between structure and activity among opioid peptides

  • Jeffrey R. Deschamps
  • Clifford George
  • Judith L. Flippen-Anderson


Since the discovery and isolation of the endogenous opioid peptides Leu- and Met-enkephalin, structural studies have been focused on deducing the bioactive conformation of the peptide ligands. Theoretically, linear peptides can have many different backbone conformations, yet early, X-ray studies on enkephalin and its analogues showed only two different backbone conformations: extended and single β-bend. More recent reports include a third conformation for Leu-enkephalin and constrained opioid peptides from two ‘new’ classes (i.e. cyclic and ‘allaromatic’ peptides). In this report the relationship between solid-state X-ray structure and opioid peptide activity is examined. The N-terminal amine nitrogen and the two aromatic rings have previously been identified as structural features important to the biological activity of opioid peptides. From X-ray studies we find that the distances between the centroids of the aromatic rings, and between the N-terminal amine nitrogen and the centroid of the phenylalanine ring, vary over a large range. There is a discernible relationship, however, between the separation of the two rings and their orientation that correlates with activity.

Key words

enkephalin neuropeptide pharmacophore X-ray diffraction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Camerman, A. and Camerman, N., In Rapaka, R.S., Barnett, G., and Hawks, L. (Eds.) Opioid Peptides: Medicinal Chemistry, NIDA, Research Monograph, 69, NIDA, Rockville, MD, 1986, pp. 351–363.Google Scholar
  2. 2.
    Griffin, J. F. and Smith, G.D., In Rapaka, R.S., Barnett, G. and Hawks, L. (Eds.) Opioid Peptides: Medicinal Chemistry, NIDA Research Monograph 87, NIDA, Rockville, MD, 1988, pp. 41–59.Google Scholar
  3. 3.
    Deschamps, J.R., George, C., and Flippen-Anderson, J.L., Biopolymers, 40 (1996) 121.PubMedCrossRefGoogle Scholar
  4. 4.
    Walker, J.M., Bowen, W.D., Walker, F.O., Matsumoto, R.R., de Costa, B. and Rice, K.C., Biol. Funct., 42 (1990) 355.Google Scholar
  5. 5.
    Schiller, P.W., In Ellis, G.P. and West, G.B. (Eds.), Progress in Medicinal Chemistry, Vol. 28, Elsevier, Amsterdam, 1991, pp. 301–340.Google Scholar
  6. 6.
    For a review see: Hruby, V.J. and Gehrig, C.A., Med. Res. Rev., 9 (1989) 343.PubMedGoogle Scholar
  7. 7.
    Schiller, P.W., In Udenfriend, S. and Meihofer, J. (Eds.) The Peptides, Vol. 6. Academic Press, Orlando, FL, 1984, pp. 219–268.Google Scholar
  8. 8.
    Temussi, P.A., Picone, D., Castigilione-Morelli M.A. Motta, A. and Tancredi, T., Biopolymers, 28 (1989) 91.PubMedCrossRefGoogle Scholar
  9. 9.
    Rapaka, R.S., In Rapaka, R.S., Barnett, G. and Hawks, L. (Eds.) Opioid Peptides: Medicinal Chemistry, NIDA Research Monograph 69, NIDA, Rockville, MD, 1986, pp. 3–20.Google Scholar
  10. 10.
    Schwyzer, R., Biochemistry, 25 (1986) 6335.PubMedCrossRefGoogle Scholar
  11. 11.
    Hansen, P.E. and Morgan, B.A., In Udenfriend, S. and Meihofer, J. (Eds.) The Peptides, Vol. 6, Academic Press, Orlando, FL, 1984, pp. 269–321.Google Scholar
  12. 12.
    Aubry, A., Birlirakis, N., Sakarellos-Daitsiotis, M., Sakarellos, C. and Marraud, M., Biopolymers, 28 (1989) 27.PubMedCrossRefGoogle Scholar
  13. 13.
    Nikiforovich, G.V., Hruby, V.J., Prakash, O. and Gehrig, C.A., Biopolymers, 31 (1991) 941.PubMedCrossRefGoogle Scholar
  14. 14.
    Mosberg, H.I., Omnaas, J.R., Lomize, A., Heyl, D.L., Nordan, I., Mousigian, C., Davis, P. and Porreca, F., J. Med. Chem. 37 (1994) 4384.PubMedCrossRefGoogle Scholar
  15. 15.
    Sheldrick, G.M., SHELXTL/PC, v. 4.2, Siemens Analytical X-ray Instruments Inc., Madison, WI, U.S.A., 1991.Google Scholar
  16. 16.
    Karle, I.L., Karle, J., Mastropaolo, D., Camerman, A. and Camerman, N., Acta Crystallogr., B39 (1983) 625.Google Scholar
  17. 17.
    Griffin, J.F., Langs, D.A., Smith, G.D., Blundell, T.L., Tickle, I.J. and Bedarkar, S., Proc. Natl. Acad. Sci. USA, 83 (1986) 3272.PubMedCrossRefGoogle Scholar
  18. 18.
    Doi, M., Tanaka, M., Ishida, T., Inoue, M., Fujiware, T., Tomita, K., Kimura, T., Sakakibara, S. and Sheldrick, G.M., J. Biochem., 101 (1987) 485.PubMedGoogle Scholar
  19. 19.
    Smith, G.D. and Griffin, J.F., Science, 199 (1978) 1214.PubMedGoogle Scholar
  20. 20.
    Ishida, T., Kenmotsu, M., Mino, Y., Inoue, M., Fujiware, T., Tomita, K., Kimura, T. and Sakakibara, S., Biochem. J., 218 (1984) 677.PubMedGoogle Scholar
  21. 21.
    Stezowski, J.J., Eckle, E. and Bajusz, S., J. Chem. Soc. Chem. Commun. 1985 (1985) 681.CrossRefGoogle Scholar
  22. 22.
    Flippen-Anderson, J.L., Deschamps, J.R., Ward, K.B., George, C. and Houghten, R., Int. J. Pept. Res., 44 (1994) 97.CrossRefGoogle Scholar
  23. 23.
    Deschamps, J.R., George, C. and Flippen-Anderson, J.L., Acta Crystallogr., C52 (1996) 1583.Google Scholar
  24. 24.
    Fournie-Zaluski, M., Prange, T., Pascard C. and Roques, B.P., Biochem. Biophys. Res. Commun., 79 (1977) 1199.PubMedCrossRefGoogle Scholar
  25. 25.
    Flippen-Anderson, J.L., George, C., Deschamps, J.R., Reddy, P.A., Lewin, A.H. and Brine, G.A., Lett. Pept. Sci., 1 (1994) 107.CrossRefGoogle Scholar
  26. 26.
    Flippen-Anderson, J.L., Hruby, V.J., Collins, N., George, C. and Cudney, B., J. Am. Chem. Soc., 116 (1994) 7523CrossRefGoogle Scholar
  27. 27.
    Lomize, A.L., Flippen-Anderson, J.L., George, C. and Mosberg, H.I., J. Am. Chem. Soc., 116 (1994) 429.CrossRefGoogle Scholar
  28. 28.
    Collins, N., Flippen-Anderson, J.L., Haaseth, R., Deschamps, J.R., George, C., Kovar, K. and Hruby, V., J. Am. Chem. Soc. 118 (1996) 2143.CrossRefGoogle Scholar
  29. 29.
    Nikiforovich, G.V., Kover, K. E., Kolodziej, S.A., Nock, B., George, C., Flippen-Anderson, J.L. and Marshall, G. R., Abstracts, 14th American Peptide Symposium, Columbus, OH, U.S.A., 1995.Google Scholar
  30. 30.
    Flippen-Anderson, J.L., Deschamps, J.R., George, C., Reddy, P.A., Lewin, A.H., Brine, G.A., Sheldrick, G., and Nikiforovitch, G., J. Pept. Res., 49 (1997) 384.PubMedCrossRefGoogle Scholar
  31. 31.
    Ciajolo, M.R., Balboni, G., Picone, D., Salvadori, S., Tancredi, T., Temussi, P.A. and Tuzi, A., Int. J. Pept. Protein Res. 46 (1995) 134.PubMedCrossRefGoogle Scholar
  32. 32.
    Deschamps, J.R., Flippen-Anderson, J.L., Moore, C., Cudney, R. and George, C., Acta Crystallogr., C53 (1997) 1478.Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Jeffrey R. Deschamps
    • 1
  • Clifford George
    • 1
  • Judith L. Flippen-Anderson
    • 1
  1. 1.Laboratory for the Structure of MatterNaval Research LaboratoryWashington, DCU.S.A.

Personalised recommendations