Parathyroid Hormone Antagonists Effective in Vivo

  • Lynn H. Caporale
  • Michael Rosenblatt
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 208)


There has long been great impetus for preparing peptide hormone antagonists effective in vivo. Pure hormone antagonists can be used to determine the mechanism of action of peptide hormones and to elucidate both the role of a hormone in normal physiology and its contribution to pathophysiology. For parathyroid hormone in particular, the impetus for generating antagonists effective in vivo includes a wide variety of therapeutic and diagnostic clinical uses in hyperparathyroid conditions (Table 1) and diagnostic utility in disorders of calcium metabolism.


Parathyroid Hormone Adenylate Cyclase Peptide Hormone Giant Cell Tumor Parathyroid Carcinoma 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. Fersht, “Enzyme Structure and Mechanism,” W. H. Freeman & Company, New York (1985).Google Scholar
  2. 2.
    W. R. Martin, Pharmacology of opioids, Pharmacology Reviews 35: 283 (1984).Google Scholar
  3. 3.
    W. H. Sawyer and M. Manning, The development of vasopressin antagonists, Federation Proc. 43: 87 (1984).Google Scholar
  4. 4.
    M. A. Ondetti and D. W. Cushman, Enzymes of the reninangiotensin system and their inhibitors, Annu. Rev. Biochem. 51: 283 (1982).CrossRefGoogle Scholar
  5. 5.
    C. S. Sweet and E. H. Blaine, Angiotensin-converting enzyme and renin inhibitors, in “Cardiovascular Pharmacology,” M. Antonaccio, ed., Raven Press. New York, (1984).Google Scholar
  6. 6.
    E. Haber, R. Zusman, J. Burton, V. J. Dzau, and A. C. Barger, Is renin a factor in the etiology of essential hypertension?, Hypertension 5: V - 8 (1983).Google Scholar
  7. 7.
    J. Boger, Renin inhibition, in “Annual Reports in Medicinal Chemistry,” Chapter 25 (in press).Google Scholar
  8. 8.
    D. F. Veber and R. M. Freidinger, The design of metabolically stable peptide analogs, Trends Neuro. Sci. 8 (in press) (1985).Google Scholar
  9. 9.
    J. T. Potts, Jr, H. M. Kronenberg, and M. Rosenblatt, Parathyroid hormone: chemistry, biosynthesis, and mode of action, Adv. Protein Chem. 35: 323 (1982).CrossRefGoogle Scholar
  10. 10.
    M. Rosenblatt, Parathyroid hormone: intracellular transport, secretion, and receptor interaction, Peptide Protein Rev. 2: 209 (1984).Google Scholar
  11. 11.
    R. B. Merrifield, Solid phase peptide synthesis. I. The synthesis of a tetrapeptide, J. Am. Chem. Soc., 85: 2149 (1963).CrossRefGoogle Scholar
  12. 12.
    A. M. Felix and M. H. Jimenez, Rapid fluorometric detection for completeness in solid phase coupling reactions, Anal. Biochem. 52: 377 (1973).CrossRefGoogle Scholar
  13. 13.
    G. A.Tyler and M. Rosenblatt, Semi-preparative high-performance liquid chromatographic purification of a 28-amino acid synthetic parathyroid hormone antagonist, J. Chromatogr. 266: 313 (1983).CrossRefGoogle Scholar
  14. 14.
    M. Rosenblatt, G. W. Tregear, G. L.Shepard, G. A. Tyler, M. Veroni, and J. T. Potts, Jr., Comparison of two solid-phase peptide syntheses of a 32-amino acid carboxyl-terminal fragment of human parathyroid hormone, hPTH-(53–84), Arch. Biochem. Biophys. 199: 286 (1980).CrossRefGoogle Scholar
  15. 15.
    G. V. Segre, M. Rosenblatt, B. L. Reiner, J. E. Mahaffey, and J. T. Potts, Jr., Characterization of parathyroid hormone receptors in canine renal cortical plasma membranes using a radioiodinated sulfur-free hormone analogue: correlation of binding with adenylate cyclase activity, J. Biol. Chem. 254: 6980 (1979).Google Scholar
  16. 16.
    J. T. Potts, Jr., G. W. Tregear, H. T. Keutmann et al., Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone, Proc. Natl. Acad. Sci. USA 1971; 68: 63 (1971).CrossRefGoogle Scholar
  17. 17.
    G. W. Tregear, J. van Rietschoten, E. Greene, H. T. Keutmann, H. D. Niall, B. Reit, J. A. Parsons, and J. T. Potts, Jr., Bovine parathyroid hormone: minimum chain length of synthetic peptide required for biological activity, Endocrinology 93: 1349 (1973).CrossRefGoogle Scholar
  18. 18.
    D. Goltzman, A. Peytremann, E. Callahan, G. W. Tregear, and J. T. Potts, Jr., Analysis of the requirements for parathyroid hormone action in renal membranes with the use of inhibiting analogues, J. Biol. Chem. 250: 3199 (1975).Google Scholar
  19. 19.
    R. J. Lefkowitz, M. G. Caron, and G. L. Stiles, Mechanisms of membrane-receptor regulation, New Engl. J. Med. 310: 1570 (1984).CrossRefGoogle Scholar
  20. 20.
    M. Rosenblatt, E. N. Callahan, J. E. Mahaffey, A. Pont, and J. T. Potts, Jr., Parathyroid hormone inhibitors: design, synthesis, and biologic evaluation of hormone analogues, J. Biol. Chem. 252: 5847 (1977).Google Scholar
  21. 21.
    M. Rosenblatt and J. T. Potts, Jr., Design and synthesis of parathyroid hormone analogues of enhanced biological activity. Endocrine Res. Commun. 14: 115 (1977).CrossRefGoogle Scholar
  22. 22.
    M. Rosenblatt, D. Goltzman, H. T. Keutmann, G. W. Tregear, and J. T. Potts, Jr., Chemical and biological properties of synthetic, sulfur-free analogues of parathyroid hormone, J. Biol. Chem. 251: 159 (1976).Google Scholar
  23. 23.
    D. A. Ausiello, M. Rosenblatt, and J-M. Dayer, Parathyroid hormone modulates protein kinase in giant cell tumors of human bone. Am. J. Physiol. 239: E144 (1980).Google Scholar
  24. 24.
    T. C. Chen, M. Rosenblatt, and J. B. Puschett, Effects of calcium on a parathyroid hormone-sensitive adenylate cyclase inhibitor, Biochem. Biophys. Res. Commun. 94: 1227 (1980).CrossRefGoogle Scholar
  25. 25.
    S. R.Goldring, J. E. Mahaffey, M. Rosenblatt, J-M. Dayer, J. T. Potts, Jr. and S. M. Krane, Parathyroid hormone inhibitors: comparison of biological activity in bone and skin-derived tissue, J. Clin. Endocrinol. Metab. 48: 655 (1979).CrossRefGoogle Scholar
  26. 26.
    S. R. Goldring, J-M. Dayer, and M. Rosenblatt, Factors regulating the response of cells cultured from human giant cell tumors of bone to parathyroid hormone, J. Clin. Endocrinol. Metab. 53: 295 (1981).CrossRefGoogle Scholar
  27. 27.
    T. Takano, H. Takigawa, E. Shirai, F. Suzuki, and M. Rosenblatt, Effects of synthetic analogs and fragments of bovine parathyroid hormone on adenosine 3′,5′-monophosphate level, ornithine decarboxylase activity, and glycosaminoglycan synthesis in rabbit costal chondrocytes in culture: structure-activity relations, Endocrinology 116: 2536 (1985)CrossRefGoogle Scholar
  28. 28.
    M. P. M. Herrmann-Erlee, J. N. M. Heersche, J. W. Hekkelman et al., Effects on bone in vitro of bovine parathyroid hormone and synthetic fragments representing residues 1--34, 2--34, and 3--34, Endocrine Res. Comm. 3: 21 (1976).CrossRefGoogle Scholar
  29. 29.
    R. A. Nissenson, S. R. Abbott, A. P. Teitelbaum, O. H. Clark, and C. D. Arnaud, Endogenous biologically active human parathyroid hormone: measurement by a guanyl nucleotide-amplified renal adenylate cyclase assay, J. Clin. Endocrinol. Metab. 52: 840 (1981).CrossRefGoogle Scholar
  30. 30.
    G. J. Strewler, R. D. Williams, and R. A. Nissenson, Human renal cancer cells produce hypercalcemia and a novel protein recognized by parathyroid hormone receptors, J. Clin. Invest. 71: 769 (1983).CrossRefGoogle Scholar
  31. 31.
    A. F. Stewart, K. L. Insogna, D. Goltzman, and A. E. Broadus, Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6-phosphate dehydrogenase-stimulating activity in extracts of tumors from patients with humoral hypercalcemia of malignancy, Proc. Natl. Acad. Sci. USA 80: 1454 (1983).CrossRefGoogle Scholar
  32. 32.
    R. E. Rizzoli, M. Somerman, T. M. Murray, and G. D. Aurbach, Binding of radioiodinated parathyroid hormone to cloned bone cells. Endocrinology 113: 1832 (1983).CrossRefGoogle Scholar
  33. 33.
    G. V. Segre, M. Rosenblatt, G. L. Tully, III, J. Laugharn, B. Reit, and J. T. Potts, Jr., Evaluation of an in vitro parathyroid hormone antagonist in vivo in dogs, Endocrinology 116: 1024 (1985).CrossRefGoogle Scholar
  34. 34.
    D. A. Gray, J. A. Parsons, J. T. Potts, Jr., M. Rosenblatt, and R. W. Stevenson, In vivo studies on an antagonist of parathyroid hormone [Nle-8,Nle-18,Tyr-34]bPTH-(3--34)amide, Br. J. Pharmacol. 76:259 (1982).Google Scholar
  35. 35.
    J. A. McGowan, T. C. Chen, J. Fragola, J. B. Puschett, and M. Rosenblatt, Parathyroid hormone: effects of the 3–34 fragment in vivo and in vitro, Science 219: 67 (1983).CrossRefGoogle Scholar
  36. 36.
    N. Horiuchi, M. Rosenblatt, H. T. Keutmann, J. T. Potts, Jr., and M. F. Holick, A multiresponse parathyroid hormone assay: an inhibitor has agonist properties in vivo. Am. J. Physiol. 244: E589 (1983).Google Scholar
  37. 37.
    K. J. Martin, E. Bellorin-Font, J. Freitag, M. Rosenblatt, and E. Slatopolski, The arterio-venous difference for immunoreactive parathyroid hormone and the production of adenosine 3′,5′-cyclic monophosphate by isolated perfused bone: studies with analogs of parathyroid hormone, Endocrinology 109: 956 (1981).CrossRefGoogle Scholar
  38. 38.
    D. G. Johnson, C. V. Goebel, V. J. Hruby, M. D. Bregman, and D. Trivedi, Science 215: 1115 (1982).CrossRefGoogle Scholar
  39. 39.
    J. A. Vilchez-Martinez, A. V. Schally, D. H. Coy, E. J. Coy, C. M. Miller, III, and A. Arimura, An in vivo assay for anti-LH-RH and anti-FSH-RH activity of inhibitory analogues of LH-RH, Endocrinology 96: 1130 (1975).CrossRefGoogle Scholar
  40. 40.
    R. Iyengar and L. Birnbaumer, Hormone receptor modulates the regulatory component of adenylyl cyclase by reducing its requirements for Mg2+ and enhancing its extent of activation by guanine nucleotides, Proc. Natl. Acad. Sci. USA 79: 5179 (1982).CrossRefGoogle Scholar
  41. 41.
    A. Gilman, G proteins and dual control of adenylate cyclase, Cell 36: 577 (1984).CrossRefGoogle Scholar
  42. 42.
    S. B. Rodan and G. A. Rodan GA, The role of Mg2+ in hormone stimulation of rat osteosarcoma adenylate cyclase, Biochim. Biophys. Acta 673: 55 (1981).CrossRefGoogle Scholar
  43. 43.
    M. Rosenblatt and J. T. Potts, Jr., Analogues of an in vitro parathyroid hormone inhibitor: modifications at the amino terminus, Calcif. Tissue Int. 33: 153 (1981).CrossRefGoogle Scholar
  44. 44.
    S. R. Nussbaum, M. Rosenblatt, and J. T. Potts, Jr., Parathyroid hormone renal receptor interactions: demonstration of two receptor-binding domains, J. Biol. Chem. 255: 10183 (1980).Google Scholar
  45. 45.
    M. Rosenblatt, G. V. Segre, G. A. Tyler, G. L. Shepard, S. R. Nussbaum, and J. T. Potts, Jr., Identification of a receptor-binding region in parathyroid hormone, Endocrinology 107: 545 (1980)CrossRefGoogle Scholar
  46. 46.
    P. L. Munson, Studies on the role of the parathyroids in calcium and phosphorus metabolism, Ann. NY Acad. Sci. 1955; 60: 776 (1955).CrossRefGoogle Scholar
  47. 47.
    N. Horiuchi, M. F. Holick, J. T. Potts, Jr., and M. Rosenblatt, A parathyroid hormone inhibitor in vivo: design and biological evaluation of a hormone analog, Science 220: 1053 (1983).CrossRefGoogle Scholar
  48. 48.
    S. Doppelt, P. Federico, G. A. Tyler, M. Rosenblatt, and R. M. Neer, Inhibition of the calcemic effects of parathyroid hormone in vivo by a hormone analogue, Calcif. Tissue Int. 35: 681 (1983).Google Scholar
  49. 49.
    G. R. Mundy, K. J. Ibbotson, S. M. D’Souza, E. L. Simpson, J. W. Jacobs, and T. J. Martin, The hypercalcemia of malignancy, New Engl. J. Med. 310: 1718 (1984).CrossRefGoogle Scholar
  50. 50.
    A. F. Stewart, R. Horst, L. J. Deftos, E. C. Cadman, R. Lang, and A. E. Broadus, Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups, New Engl. J. Med. 303: 1377 (1980).CrossRefGoogle Scholar
  51. 51.
    D. Goltzman, A. F. Stewart, and A. E. Broadus, Malignancy-associated hypercalcemia: evaluation with a cytochemical bioassay for parathyroid hormone, J. Clin. Endocrinol. Metab. 53: 899 (1981).CrossRefGoogle Scholar
  52. 52.
    L. H. Caporale, P. DeHaven, G. A. Tyler, and M. Rosenblatt, Discrimination between parathyroid hormone (PTH) agonists and antagonists in vitro: modification of the renal membrane adenylate cyclase assay to reflect in vivo activity of PTH analogs. American Society for Bone and Mineral Research Seventh Annual Scientific Meeting Program, Abstract 304 (1985).Google Scholar
  53. 53.
    J. Rudinger, The design of peptide hormone analogs, in “Drug Design,” Vol. 2, E. J. Ariens, ed., Academic Press, New York (1971).Google Scholar
  54. 54.
    D. F. Veber, R. Saperstein, R. F. Nutt et al., A super active cyclic hexapeptide analog of somatostatin, Life Sci. 34: 1371 (1984).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Lynn H. Caporale
    • 1
  • Michael Rosenblatt
    • 1
  1. 1.Merck Sharp & Dohme Research LaboratoriesWest PointUSA

Personalised recommendations