Advertisement

Suppression of Gonadotropin Release and Ovulation in Animals by Inhibitory Analogs of Luteinizing Hormone-Releasing Hormone

  • David H. Coy
  • Esther J. Coy
  • Jesus A. Vilchez-Martinez
  • Antonio de la Cruz
  • Akira Arimura
  • Andrew V. Schally
Part of the Current topics in Molecular Endocrinology book series (CTME, volume 3)

Abstract

The basic assumption in developing competitive inhibitors of luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH), the structure of which is shown in Figure 1, was that analogs could be designed which could retain the ability to bind to pituitary receptor sites whilst being devoid of gonadotropin-releasing activity. The first indication that this approach was valid came out of work by Vale et al. (1972) who found that removal of histidine from the peptide chain gave a nonapeptide of very low LH-RH activity which was capable of inhibiting the action of LH-RH on cultures of anterior pituitary cells. This inhibition was, however, weak and subsequently could not be demonstrated in vivo in rats (Vilchez-Martinez et al., 1974a). Other inhibitors based on the original decapeptide sequence were shown (Vilchez-Martinez et al., 1974a) to be active in vivo; however, these were also too weak to be of practical value. It became obvious, therefore, that ways must be found to substantially raise the binding affinity of an inhibitor, again without increasing agonistic activity to any great extent.

Keywords

Agonistic Activity Anterior Pituitary Cell Lower Dose Level Saline Administration Gonadotropin Release 
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. Arimura, A., Vilchez-Martinez, J.A., Coy, D.H., Coy, E.J., Hirotsu, Y., and Schally, A.V. (1974) Endocrinology 95, 1174–1177.PubMedCrossRefGoogle Scholar
  2. Corbin, A., and Beattie, C.W. (1975) Endocrine Res. Commun. 2, 1–23.CrossRefGoogle Scholar
  3. Coy, D.H., Coy, E.J., Schally, A.V., Vilchez-Martinez, J.A., Debeljuk, L., Carter, W.H., and Arimura, A. (1974a) Biochemistry 13, 323–326.PubMedCrossRefGoogle Scholar
  4. Coy, D.H., Coy, E.J., Schally, A.V., Vilchez-Martinez, J.A., Hirotsu, Y., and Arimura, A (1974b) Biochem. Biophys. Res. Commun. 57, 335–340.PubMedCrossRefGoogle Scholar
  5. Coy, D.H., Vilchez-Martinez, J.A., Coy, E.J., Arimura, A., and Schally, A.V. (1976), J. Med. Chem., in press.Google Scholar
  6. Coy, D.H., Vilchez-Martinez, J.A., Coy, E.J., Nishi, N., Arimura, A., and Schally, A.V. (1975) Biochemistry 14, 1848–1851.PubMedCrossRefGoogle Scholar
  7. de la Cruz, A., Arimura, A., and Schally, A.V. (1976a) Endocrinology, in press.Google Scholar
  8. de la Cruz, A., Coy, D.H., Schally, A.V., Coy, E.J., de la Cruz, K.G., and Arimura, A. (1975) Proc.Soc.Exp.Biol.Med. 149, 576–579.Google Scholar
  9. de la Cruz, A., Coy, D.H., Vilchez-Martinez, A.J., Arimura, A., and Schally, A.V. (1976), Science, in press.Google Scholar
  10. Foell, T.J. and Yardley, J.P. (1974) U.S. Patent 3,855,199.Google Scholar
  11. Fujino, M., Fukuda, T., Shinagawa, S., Kobayashi, S., Yamakazi, I., Nakagama, R., Seely, J.H., White, W.F., Rippel, R.H. (1974a) Biochem.Biophys. Res.Commun. 60, 406–413.PubMedCrossRefGoogle Scholar
  12. Fujino, M., Kobayashi, S., Obayashi, M., Shinagawa, S., Fukuda, T., Kitada, C., Nakagawa, R., Yamakazi, I., White, W.F., and Rippel, R.H. (1972) Biochem.Biophys.Res.Commun. 49, 863–869.PubMedCrossRefGoogle Scholar
  13. Fujino, M., Yamakazi, S., Kobayashi, S., Fukuda, T., Shinagawa, S., Nakayama, R., White, W.F., and Rippel, R.H. (1974) Biochem. Biophys. Res. Commun. 57, 1248–1256.PubMedCrossRefGoogle Scholar
  14. Monahan, M., Amoss, M.S., Anderson, H.A., and Vale, W. (1973), Biochemistry 12, 4616–4620.PubMedCrossRefGoogle Scholar
  15. Rees, R.W.A., Foell, T.J., Chai, S.Y., and Grant, N. (1974) J.Med. Chem..17, 1016–1019.PubMedCrossRefGoogle Scholar
  16. Vale, W., Grant, G., Rivier, J., Monahan, M., Amoss, M., Blackwell, R., Burgus, R., and Guillemin, R. (1972). Science 176, 933–934.PubMedCrossRefGoogle Scholar
  17. Vilchez-Martinez, J.A., Coy, D.H., Arimura, A., Coy, E.J., Hirtosu, Y., and Schally, A.V. (1974c) Biochem.Biophys.Res.Commun. 59, 1226–1232.PubMedCrossRefGoogle Scholar
  18. Vilchez-Martinez, J.A., Coy, D.H., Coy, E.J., Arimura, A., and Schally, A.V. (1976) Endocrinology, in press.Google Scholar
  19. Vilchez-Martinez, J.A., Coy, D.H., Coy, E.J., Schally, A.V., and Arimura, A. (1975) Fert.Ster. 26, 554–559.Google Scholar
  20. Vilchez-Martinez, J.A., Schally, A.V., Coy, D.H., Coy, E.J., Debeljuk, L., and Arimura, A. (1974b) Endocrinology 95, 213–218.PubMedCrossRefGoogle Scholar
  21. Vilchez-Martinez, J.A., Schally, A.V., Debeljuk, L., Coy, D.H., Coy, E.J., Arimura, A., and Yanaihara, N. (1974a) Neuroendocrinol. 14, 121–128.CrossRefGoogle Scholar
  22. Zeballos, G. and McCann, S.M. (1975) Endocrinology 96, 1377–1385.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1976

Authors and Affiliations

  • David H. Coy
    • 1
  • Esther J. Coy
    • 1
  • Jesus A. Vilchez-Martinez
    • 1
  • Antonio de la Cruz
    • 1
  • Akira Arimura
    • 1
  • Andrew V. Schally
    • 1
  1. 1.Department of Medicine, Veterans Administration HospitalTulane Univ. School of MedicineNew OrleansUSA

Personalised recommendations