Antagonists for Substance P and Other Neurokinins

  • D. Regoli
  • J. Mizrahi
  • P. d’Orleans-Juste
  • S. Dion
  • G. Drapeau
  • E. Escher
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)

Abstract

Because of the numerous roles of neurokinins in physiology and physiopathology, antagonists for these peptides represent a new type of promising pharmacological tool (Rosell and Folkers, 1982). During the last 5 years, a fairly large number of compounds have been developed by various investigators (see references in Table I), and some prototypes of the various categories (undeca-, octa-, hepta-, or hexapeptides) are presented in Table I. From these results, it is evident that (1) all antagonists contain at least two D-amino acids (generally D-Trp in the positions 7 and 9), which are needed to confer to the peptide its antagonistic properties, (2) the N-terminal residues (either the first or the second) are replaced with D isomers (D-Arg1, D-Pro2 in the undecapeptide, D-Pro4 in the octapeptides) or with L isomers (Arg or Pro in the hepta and hexapeptides) in order to protect the antagonist from degradation or improve its solubility, and (3) the C-terminal Met has generally been replaced with an aliphatic (Leu, Nle) or aromatic (Phe) residue to increase the affinity of undeca-, octa-, and heptapeptide antagonists.

Keywords

Flare Angiotensin Histamine Acetylcholine Vasopressin 

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References

  1. Arunlakshana, O. and Schild, H. O., 1959, Some quantitative uses of drug antagonists, Br. J. Pharmacol. 14:48–58.Google Scholar
  2. Baizman, E. R., Gordon, T. D., Hansen, P. E., Kiefer, D., Lopresti, D. M., McKay, F. C., Morgan, B. A., and Perrone, W. H., 1983, Structure and antagonist activity in a series of hexapeptide substance P analogs, in: Peptides: Structure and Function (J. V. Hruby, and D. H. Rich, eds.) Pierce Chemical, Rockford, IL, pp. 437–440.Google Scholar
  3. Buck, S. H., Burcher, E., Shults, C. W., Lovenberg, W., and O’Donohue, T. L., 1984, Novel pharmacology of substance K-binding sites: A third type of tachykinin receptor, Science 226:987–989.PubMedCrossRefGoogle Scholar
  4. Devillier, P., Renoux, M., Giroud, J.-P., and Regoli, D., 1985, Peptides and histamine release from rat peritoneal mast cells, Eur. J. Pharmacol. 117:89–96.PubMedCrossRefGoogle Scholar
  5. Folkers, K., Häkanson, R., Hörig, J., Xu, J. C. and Leander, S., 1984, Biological evolution of substance P antagonists, Br. J. Pharmacol. 83:449–456.PubMedGoogle Scholar
  6. Foreman, J.-C., and Jordan, C. C., 1983, Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin, J. Physiol. (Lond.) 335:449–465.Google Scholar
  7. Foreman, J.-C., Jordan, C.-C., and Piotrowski, W., 1982, Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin, Br. J. Pharmacol. 77:531–539.PubMedGoogle Scholar
  8. Fosbraey, P., Featherstone, R.-L., and Morton, I. K. M., 1984, Comparison of potency of substance P and related peptides on [3H]-acetylcholine release and contractile actions in the guinea pig ileum, Naunyn Schmiedebergs Arch. Pharmacol. 326: 111-115.Google Scholar
  9. Hörig, J. A., and Schultheiss, H., 1984, Structure-activity relationship of C-terminal hexa-and hep-tapeptide substance P antagonists as studied in the guinea pig ileum, Eur. J. Pharmacol. 105:65–72.PubMedCrossRefGoogle Scholar
  10. Hunter, J. C., and Maggio, J. E., 1984, A pharmacological study with substance K: Evidence for multiple types of tachykinin receptors, Eur. J. Pharmacol. 105:149–153.PubMedCrossRefGoogle Scholar
  11. Jensen, R. T., Jones, S. W., Folkers, K., and Gardner, J. D., 1984a, A synthetic peptide that is a bombesin receptor antagonist, Nature 309:61–63.PubMedCrossRefGoogle Scholar
  12. Jensen, R. T., Jones, S. W., Lu, Y. A., Xu, J. C., Folkers, K., and Gardner, J. D., 1984b, Interaction of substance P antagonists with substance P receptors on dispersed pancreatic acini, Biochim. Biophys.Acta 804:181–191.PubMedCrossRefGoogle Scholar
  13. Kangawa, K., Minamino, N., Fukuda, A., and Matsuo, H., 1983, Neuromedin K: A novel mammalian tachykinin identified in porcine spinal cord, Biochem. Biophys. Res. Commun. 114:533–540.PubMedCrossRefGoogle Scholar
  14. Lee, C. M., Iversen, L. L., Hanley, M. R., and Sandberg, B. E. B., 1982, The possible existence of multiple receptors for substance P, Nauyn Schmiedebergs Arch. Pharmacol. 318:281–287.CrossRefGoogle Scholar
  15. Mizrahi, J., Escher, E., D’Orléans-Juste, P., and Regoli, D., 1984, Undeca-and octa-peptide antagonists for substance P; a study on the guinea pig trachea, Eur. J. Pharmacol. 99:193–202.PubMedCrossRefGoogle Scholar
  16. Mizrahi, J., Dion, S., D’Orléans-Juste, P., Escher, E., and Regoli, D., 1985a, Tachykinin receptors in smooth muscles: A study with agonists (substance P, neurokinin A) and antagonists, Eur. J. Pharmacol. 118:25–36.PubMedCrossRefGoogle Scholar
  17. Mizrahi, J., Dion, S., D’Orléans-Juste, P., and Regoli, D., 1985b, Activities and antagonism of bombesin on urinary smooth muscles, Eur. J. Pharmacol. 111:339–345.PubMedCrossRefGoogle Scholar
  18. Nawa, H., Dotenchi, M., Igano, K., Inouye, K., and Nakanishi, S., 1983, Substance K: A novel mammalian tachykinin that differs from substance P in its pharmacological profile, Life Sci. 34:1153–1160.CrossRefGoogle Scholar
  19. Regoli, D., Escher, E., and Mizrahi, J., 1984a, Structure-activity studies and the development of antagonists, Pharmacology 28:301–320.PubMedCrossRefGoogle Scholar
  20. Regoli, D., Mizrahi, J., D’Orléans-Juste, P., and Escher, E., 1984b, Receptors for Substance P. II. Classification by agonists fragments and analogues, Eur. J. Pharmacol. 97:171–177.PubMedCrossRefGoogle Scholar
  21. Regoli, D., Mizrahi, J., D’Orléans-Juste, P., Dion, S., Drapeau, G., and Escher, E., 1985, Substance P antagonists showing selectivity for different receptor types, Eur. J. Pharmacol. 109:121–125.PubMedCrossRefGoogle Scholar
  22. Rosell, S., and Folkers, K., 1982, Substance P antagonists: A new type of pharmacological tool, Trends Pharmacol. Sci. 3:211–212.CrossRefGoogle Scholar
  23. Schild, O. H., 1973, Receptor classification with special reference to beta-adrenergic receptors, in: Drug Receptors (H. P. Rang, ed.), University Park Press, Baltimore, pp. 29–36.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • D. Regoli
    • 1
  • J. Mizrahi
    • 1
  • P. d’Orleans-Juste
    • 1
  • S. Dion
    • 1
  • G. Drapeau
    • 1
  • E. Escher
    • 1
  1. 1.Department of Pharmacology, Medical SchoolUniversity of SherbrookeSherbrookeCanada

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