Skip to main content
SpringerLink
Log in

Potent and Selective Oxytocin Antagonists Obtained by Chemical Modification of a Streptomyces Silvensis Derived Cyclic Hexapeptide and by Total Synthesis

  • Chapter
Chemical Aspects of Enzyme Biotechnology

Abstract

Oxytocin (OT) is a neurohypophyseal hormone which has an important function in parturition.1 There is considerable evidence that the uterotonic action of OT and its stimulation of uterine prostaglandin release combine to initiate labor.2,3 Additionally, OT mediates the postpartum function of contracting the mammary myoepithelium to elicit milk letdown4 and has also recently been implicated as a key element in preterm labor.5,6 Attempts to further delineate these OT connected events have provided the impetus to discover agents which interact selectively and competitively at the OT receptor. Such compounds are invaluable in determining the physiological and pathophysiological role of OT and its close structurally related hormone, arginine vasopressin (AVP). Additional interest derives from the prospect of their use as novel therapeutic agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Pritchard, J. A.; MacDonald, P. C.; Gant, N. F.; in Williams Obstetrics; Appleton-Century-CroftsiNorwalk, 1985, ed.17, 295.

    Google Scholar 

  2. Fuchs, A.; Fuchs, F.; Husslein, P.; Soloff, M. S.; Fernstrom, M. J. Science (Washington, D.C.) (1982) 215, 1396.

    Article  CAS  Google Scholar 

  3. Chan, W. Y.; Powell, A. M.; Hruby, V. J. Endocrinology (1982) 111(1) 48.

    Article  PubMed  CAS  Google Scholar 

  4. Soloff, M. S.; Alexandrova, M.; Fernstrom, M. J. Science (Washington, D.C.) (1979) 204, 1313.

    Article  CAS  Google Scholar 

  5. Chan, W. Y.; Hruby, V. J.; Rockway, T. W.; Hlavacek, J. J. Exp. Ther. Pharmacol, (1986) 239, 84.

    CAS  Google Scholar 

  6. Akerlund, M.; Stromberg, P.; Hauksson, A.; Andersen, L. F.; Lyndrup, J.; Trojnar, J.; Melin, P. Br. J. Obstet. Gynaecol. (1987) 94, 1040.

    Article  CAS  Google Scholar 

  7. Berde, B.; Boissonnas, R. A. in Neurohypophysial Hormones and Similar Polypeptides, Berde, B., Ed.; Springer Verlag: Berlin; 1968; p 802.

    Google Scholar 

  8. Sawyer, W. H.; Manning, M. in Oxytocin: Clinical and Laboratory Studies, Amico, J. A.; Robinson, A. G., Eds.; Elsevier Science Publishers B. V. (Biomedical Division): Amsterdam; 1985; p 423.

    Google Scholar 

  9. Manning, M.; Sawyer, W. H. J. Lab. Clin. Med. (1989) 114(6), 617.

    PubMed  CAS  Google Scholar 

  10. Manning, M.; Sawyer, W. H. Trends Neurosci. (1984) 7, 6.

    Article  CAS  Google Scholar 

  11. Chan, W. Y.; Nestor, J. J.; Ferger, M. F.; du Vigneaud, V. Proc. Soc. Exp. Biol. Med. (1974) 146, 364.

    Article  PubMed  CAS  Google Scholar 

  12. Kruszynski, M.; Lammek, B.; Manning, M.; Seto, J.; Haldar, J.; Sawyer, W. H. J. Med. Chem. (1980) 23, 364.

    Article  PubMed  CAS  Google Scholar 

  13. Chan, W. Y.; Fear, R.; du Vigneaud, V. Endocrinology (1967) 81, 1267.

    Article  PubMed  CAS  Google Scholar 

  14. Melin, P.; Trojnar, J.; Johansson, B.; Vilhardt, H.; Akerlund, M. J. Endocrinol. (1986) 111, 125.

    Article  PubMed  CAS  Google Scholar 

  15. Hahn, D. W.; Demarest, K. T.; Ericson, R.; Homm, R. E.; Capetola, R. J.; McGuire, J. L. Am. J. Obstet. Gynecol. (1987) 157, 977.

    PubMed  CAS  Google Scholar 

  16. Andersen, L. F.; Lyndrup, J.; Akerlund, M.; Melin, P. Am. J. Perinat. (1989) 6(2), 196.

    Article  CAS  Google Scholar 

  17. Pettibone, J. D.; Clineschmidt, B.V.; Anderson, P. S.; Freidinger, R. M.; Lundell, G. F.; Koupal, L. R.; Schwartz, C. D.; Williamson, J. M.; Goetz, M. A.; Hensens, O. D.; Liesch, J. M.; Springer, J. P. Endocrinology (1989) 125(1), 217.

    Article  PubMed  CAS  Google Scholar 

  18. Mattingly, P. G.; Miller, M. J. J. Org. Chem. (1980) 45, 410.

    Article  CAS  Google Scholar 

  19. Pitzenberger, S. M.; unpublished results.

    Google Scholar 

  20. Springer, J. P.; personal communication.

    Google Scholar 

  21. To be reported in the full account.

    Google Scholar 

  22. Sherman, D. B.; Spatola, A. F. J. Amer. Chem. Soc. (1990) 112, 433.

    Article  CAS  Google Scholar 

  23. Lajoie, G.; Lepine, F.; Maziak, L.; Belleau, G. Tet. Lett. (1983) 24(36), 3815.

    Article  CAS  Google Scholar 

  24. Crystals for X-ray diffraction studies formed from ethanol in space group P21 with cell constants of a=10.413, b=17.225, c=11.199 and b=97.77R. The final unweighted refinement residual is 0.067.

    Google Scholar 

  25. Ball, R. G. Acta Crystallogr. (1990), to be submitted.

    Google Scholar 

  26. Szelke, M.; Leckie, B.; Hallett, A.; Jones, D. M.; Sueiras, J.; Atrash, B.; Lever, A. F. Nature (London) (1982) 299, 555.

    Article  CAS  Google Scholar 

  27. Rodriguez, M.; Bali, J.-P.; Magous, R.; Castro, B.; Martinez, J. Int. J. Peptide Protein Res. (1989) 27, 293.

    Article  Google Scholar 

  28. Coy, D. H.; Heinz-Erian, P.; Jiang, N.-Y.; Sasaki, Y.; Taylor, J.; Moreau, J.-P.; Wolfrey, W. T.; Gardner, J. D.; Jensen, R. T. J. Biol. Chem. (1988) 263(11), 5056.

    PubMed  CAS  Google Scholar 

  29. Anteunis, M. J. O.; Van Der Auwera, C. Int. J. Pept. Prot. Res. (1988) 31, 301.

    Article  CAS  Google Scholar 

  30. Nutt, R. F.; Holly, F. W.; Homnick, C.; Hirschmann, R.; Veber, D. F. J. Med. Chem. (1981) 24, 692.

    Article  PubMed  CAS  Google Scholar 

  31. Brady, S. F.; Varga, S. L.; Freidinger, R. M.; Schwenk, D. A.; Mendlowski, M.; Holly, F. W.; Veber, D. F. J. Org. Chem. (1979) 44, 3101.

    Article  CAS  Google Scholar 

  32. Hassall, C. H.; Johnson, W. H.; Theobold, C. H. J. C. S. Perkin I (1979) 1451.

    Google Scholar 

  33. Caldwell, C. G.; manuscript in preparation.

    Google Scholar 

  34. Felder, E.; Maffei, S.; Pietra, S.; Pitre, D. Helv. Chim. Acta (1960) 43, 888.

    Article  CAS  Google Scholar 

  35. Cheng, Y.-C.; Prusoff, W. H. Biochem. Pharmacol. (1973) 22, 3099.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicinal Chemistry, Merck, Sharp & Dohme Research Laboratories, West Point, Pennsylvania, 19486, USA

    M. G. Bock, R. M. DiPardo, P. D. Williams, R. D. Tung, J. M. Erb, N. P. Gould, W. L. Whitter, D. S. Perlow, G. F. Lundell, D. F. Veber & R. M. Freidinger

  2. Departments of Biophysical Chemistry, Merck, Sharp & Dohme Research Laboratories, West Point, Pennsylvania, 19486, USA

    R. G. Ball

  3. New Lead Pharmacology, Merck, Sharp & Dohme Research Laboratories, Rahway, New Jersey, 07065, USA

    D. J. Pettibone & B. V. Clineschmidt

Authors
  1. M. G. Bock
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. M. DiPardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. D. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. D. Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. M. Erb
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. P. Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. L. Whitter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. S. Perlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. F. Lundell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. G. Ball
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D. J. Pettibone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. B. V. Clineschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D. F. Veber
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R. M. Freidinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Texas A&M University, College Station, Texas, USA

    Thomas O. Baldwin , Frank M. Raushel  & A. Ian Scott ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Springer Science+Business Media New York

About this chapter

Cite this chapter

Bock, M.G. et al. (1990). Potent and Selective Oxytocin Antagonists Obtained by Chemical Modification of a Streptomyces Silvensis Derived Cyclic Hexapeptide and by Total Synthesis. In: Baldwin, T.O., Raushel, F.M., Scott, A.I. (eds) Chemical Aspects of Enzyme Biotechnology. Industry-University Cooperative Chemistry Program Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9637-7_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-4757-9637-7_11

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4757-9639-1

  • Online ISBN: 978-1-4757-9637-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation