New Concepts in Peptide Analog Design

  • Peter W. Schiller
Part of the Biochemical Endocrinology book series (BIOEND)


Many peptide hormones and neurotransmitters exert their various biological effects through interaction with several distinct receptor types. The design and synthesis of peptide analogs with high specificity for a particular receptor class and with altered “efficacy” (antagonists or superagonists) represent major goals in peptide drug development. The classical approach based on amino acid substitutions, deletions or additions has been used for more than three decades in peptide analog design and in many cases has permitted the development of antagonists or of more specific receptor ligands. It still represents the method of choice for determining initial structure-activity relationships with a newly discovered peptide hormone or neurotransmitter. In recent years our increasing knowledge of the receptors interacting with biologically active peptides has led to new design principles. In particular, new design concepts based on the distinct conformational requirements, proposed different membrane environment and putative proximity relationships of the different receptor classes interacting with a given peptide hormone or neurotransmitter have been developed.


Opioid Peptide Receptor Affinity Opiate Receptor Peptide Analog Receptor Selectivity 


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  1. Berman, J.M., Goodman, M., Nguyen, T.M.-D., and Schiller, P.W., 1983, Cyclic and acyclic partial retro-inverso enkephalins: μ-receptor selective enzyme resistant analogs, Biochem. Biophys. Res. Commun., 115:864.Google Scholar
  2. DiMaio, J., and Schiller, P.W., 1980, A cyclic enkephalin analog with high in vitro opiate activity, Proc. Natl. Acad. Sci. USA, 77:7162.Google Scholar
  3. DiMaio, J., Nguyen, T.M.-D., Lemieux, C., and Schiller, P.W., 1982, Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effect of conformational constraints on opiate receptor selectivity, J. Med. Chenu, 25:1432.Google Scholar
  4. Edwards, J.V., Spatola, A.F., Lemieux, C., and Schiller, P.W., 1986, In vitro activity profiles of cyclic and linear enkephalin pseudopeptide analogs, Biochem. Biophys. Res. Commun., 136:730.Google Scholar
  5. Franklin, T.J., 1980, Binding energy and the activation of hormone receptors, Biochem. Pharmaco1., 29:853.CrossRefGoogle Scholar
  6. Handa, B.K., Lane, A.C., Lord, J.A.H., Morgan B.A., Rance, M.J., and Smith, C.F.C., 1981, Analogues of β-LPH61–64 possessing selective agonist activity at u-opiate receptors, Eur. J. Pharmacol., 70:531.Google Scholar
  7. Lee, N.M., and Smith, A.P., 1980, A protein-lipid model of the opiate receptor, Life Sci., 26:1459.PubMedCrossRefGoogle Scholar
  8. Lord, J.A.H., Waterfield, A.A., Hughes, J., and Kosterlitz, H.W., 1977, Endogenous opioid peptides: multiple agonists and receptors, Nature (London), 267:495.CrossRefGoogle Scholar
  9. Lutz, R.A., Cruciani, R.A., Shimohigashi, Y., Costa, T., Kassis, S., Munson, P.J., and Rodbard, D., 1985, Increased affinity and selectivity of enkephalin tripeptide (Tyr-D-Ala-Gly) dimers, Eur. J. Pharmacol., 111:257.Google Scholar
  10. Mosberg, H.I., Hurst, R., Hruby, V.J., Gee, K., Yamamura, H.I., Galligan, J.J., and Burks, T.F., 1983, Bis-penicillamine enkephalins possess highly improved specificity toward 6-opioid receptors, Proc. Natl. Acad. Sci. USA, 80:5871.Google Scholar
  11. Schiller, P.W., 1984, Conformational analysis of enkephalin and conformation-activity relationships, in “The Peptides: Analysis, Synthesis, Biology”, Vol. 6, S. Udenfriend and J. Meienhofer, eds., Academic Press, Orlando, F1., pp. 219–268.Google Scholar
  12. Schiller, P.W., and DiMaio, J., 1982, Opiate receptor subclasses differ in their conformational requirements, Nature (London), 297:74.CrossRefGoogle Scholar
  13. Schiller, P.W., and DiMaio, J., 1983, Aspects of conformational restriction in biologically active peptides, in “Peptides: Structure and Function”, V.J. Hruby and D.H. Rich, eds-, Pierce Chemical Company, Rockford, 111., pp. 269–278.Google Scholar
  14. Schiller, P.W., and Nguyen, T.M.-D., 1984, Activity profiles of novel side chain-to-side chain cyclized opioid peptide analogs, Neuropetpides, 5:165.CrossRefGoogle Scholar
  15. Schiller, P.W., Eggimann, B., DiMaio, J., Lemieux, C., and Nguyen, T.M.-D., 1981, Cyclic enkephalin analogs containing a cystine bridge, Biochem. Biophys. Res. Commun., 101:337.Google Scholar
  16. Schiller, P.W., Nguyen, T.M.-D., DiMaio, J., and Lemieux, C., 1983, Comparison of μ-, δ and ϰ-receptor binding sites through pharmacologic evaluation of p-nitrophenylalanine analogs of opioid peptides, Life Sci., 33: 319.PubMedCrossRefGoogle Scholar
  17. Schiller, P.W., DiMaio, J., and Nguyen, T.M.-D., 1985a, Activity profiles of conformationally restricted opioid peptide analogs, in “Proc. 16th FEBS Meeting”, Part B, Y.A. Ovchinnikov, ed., VNU Science Press, Utrecht, The Netherlands, pp. 457–462.Google Scholar
  18. Schiller, P.W., Nguyen, T.M.-D., and Miller, J., 1985b, Synthesis of side chain-to-side chain cyclized peptide analogs on solid supports, Int. J. Peptide Protein Res., 25:171.Google Scholar
  19. Schiller, P.W., Nguyen, T.M.-D., Maziak, L.A., and Lemieux, C., 1985c, A novel cyclic opioid peptide analog showing high preference for μ-receptors, Biochem. Biophys. Res. Commun., 127:558.Google Scholar
  20. Schiller, P.W., Nguyen, T.M.-D., Maziak, L.A., Wilkes, B.C., and Lemieux, C., 1987a, Structure-activity relationships of cyclic opioid peptide analogues containing a phenylalanine residue in the 3-position, J. Med. Chem., 30:2094.Google Scholar
  21. Schiller, P.W., Nguyen, T.M.-D., Lemieux, C., Larson, D.L., Ronsisvalle, G., Takemori, A.E., and Portoghese, P.S., 1987b, Synthesis and activity profiles of bivalent [Leu5]enkephalin-α-oxymorphamine hybrid opioid receptor ligands, in “Peptides: Structure and Function”, G.R. Marshall, C.M. Deber and K.D. Kopple, eds., Escom Science Publishers, Leiden, The Netherlands, in press.Google Scholar
  22. Schwyzer, R., 1986, Molecular mechanism of opioid receptor selection, Biochemistry, 25:6335.PubMedCrossRefGoogle Scholar
  23. Shimohigashi, Y., Costa, T., Matsuura, S., Chen, H.-C., and Rodbard, D., 1982a, Dimeric enkephalins display enhanced affinity and selectivity for the delta opiate receptor, Mol. Pharmacol., 21:558.Google Scholar
  24. Shimohigashi, Y., Costa, T., Chen, H.-C., and Rodbard, D., 1982b, Dimeric tetrapeptide enkephalins display extraordinary selectivity for the δ opiate receptor, Nature (London), 297:333.CrossRefGoogle Scholar
  25. Smith, C.F.C., and Rance, M.J., 1983, Opiate receptors in the rat vas deferens Life Sci., 33:327.PubMedCrossRefGoogle Scholar
  26. Vaught, J.L., Rothman, R.B., and Westfall, T.C., 1982, Mu and delta receptors: their role in analgesia and in the differential effects of opioid peptides on analgesia, Life Sci., 30:1443.PubMedCrossRefGoogle Scholar
  27. Wilkes, B.C., and Schiller, P.W., 1987a, Theoretical conformational analysis of a u-selective cyclic opioid peptide analog, Biopolymers, 26:1573.CrossRefGoogle Scholar
  28. Wilkes, B.C., and Schiller, P.W., 1987b, Theoretical conformational analysis of u-selective cyclic analogs, In “Peptides: Structure and Function”, G.R. Marshall, C.M. Deber and K.D. Kopple, eds., Escom Science Publishers, Leiden, The Netherlands, in press.Google Scholar
  29. Zajac, J.M., Gacel, G., Petit, F., Dodey, P., Rossignol, P., and Roques, B., 1983, Deltakephalin: Tyr-D-Thr-Gly-Phe-Leu-Thr: A new highly potent and fully specific agonist for opiate u-receptors, Biochem. Biophys. Res. Commun., 111:390.Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Peter W. Schiller
    • 1
  1. 1.Laboratory of Chemical Biology and Peptide ResearchClinical Research Institute of MontrealMontrealCanada

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