1. Field of the Invention
Within the general area of hormone regulation this invention relates to the synthesis and use of synthetic hormone complexes. These complexes have as one component a peptide which confers binding specificity for hormone or regulatory factor receptors on or in a cell and as a second component a structure which alters second messenger mobilization by the cell. Therefore, one aspect of this invention is a synthetic hormone complex which binds to specific receptors on the surface of or in a particular type of cell and causes either an increase or a decrease in second messenger mobilization by the cell. One such second messenger molecule is calcium ion. A change in calcium ion mobilization results in altered cellular function. This ability to alter cell functions includes any physiological response dependent upon the binding of a polypeptide hormone and a change in calcium mobilization. Other physiological references are dependent upon other second messenger molecules such as cyclic adenosine monophosphate or cyclic guanosine monophosphate. Among the many peptide hormones two classes, the releasing or the release inhibiting hormones, are of particular importance since these classes regulates the function of major hormone systems.
2. Description of the Prior Art
Endocrinologists have long desired to be able to selectively regulate the release of specific hormones as they are released from the animals own hormone producing cells. In part it has been possible to administer to the animal supplemental quantities of a desired hormone or hormone analogue, such as insulin or one of the steroid hormones. However, many hormones are either not available in sufficient quantities, too expensive, evoke immune responses or must be administered in such a highly regulated manner that it is not feasable to use them. In addition, there has been no easy or safe method for removing or reducing the effective or actual concentration of one specific hormone produced in vivo. Calcium ion channel antagonists are known to block calcium ion incorporation non-specifically, that is, for all cell types. Such systemic administration of a calcium ion channel inhibitor is often unacceptable since it alters the physiology of all systems and disrupts basic functions necessary for life, although cardiac drugs such as verapamil have been successful. However, the development of a "targeted" calcium inhibitor would be much more acceptable since the systemic concentration would be quite low and only the cell type "targeted" would receive a dosage sufficient to alter its physiology significantly.
Our present understanding of the regulation and control of hormone release indicates there is a central function played by the class of hormones or factors that modulate normal in vivo release of other hormones. These regulatory hormones or factors are referred to as releasing, stimulating or inhibiting hormones or factors. Pituitary gland regulation of hormone release is a particularly well documented example of the importance of these regulatory hormones. The ability to modulate, either up or down, the release of hormones in vivo would provide the endocrinologist with a tool for optimizing the level of specific hormones. Therefore, there is a need for both hormone agonists and hormone antagonists. Such targeted agonists can be used to overcome metabolic blocks caused not by failure of endocrine synthesis, but by failure to release hormone into the blood. Similarly, overactive endocrine function can be specifically blocked through the use of targeted antagonists which block the release of excessive amounts of a specific hormone. Moreover, such methods, if precisely targeted involve in vivo modulation of only one hormone system and are less likely to disrupt general endocrine homeostasis. Such methods might be useful in treating hormonal imbalance or dysfunction causing disesase, regulating fertility, optimizing growth and meat production, compensating for the effects of non-hormonal diseases and partially alleviating some of the side effects of aging.
References which relate to the subject invention are:
1. Conn et al, Life Sciences U.S.A., vol 24: 2461, (1979). PA0 2. Marian et al, Molecular Pharmacology U.S.A., vol 16: 196, (1979). PA0 3. Conn et al, Endocrinology U.S.A., vol 105: 1122, (1979). PA0 4. Conn et al, Cell Calcium U.K., vol 1: 7, (1980). PA0 5. Marian et al, Life Sciences U.S.A., vol 27: 87, (1980). PA0 6. Conn et al, Endocrinol. U.S.A., vol. 107: 2133, (1980). PA0 7. Conn et al, Nature UK, vol 292: 264, (1981). PA0 8. Conn et al, Endocrine Reviews U.S.A., vol. 2: 174, (1981). PA0 9. Hazum et al, Proc. Natl. Acad. Sci. U.S.A., vol. 77: 6695, (1980). PA0 10. Conn et al, Endocrinology U.S.A., 109: 1122 (1981). PA0 11. Marian et al, Molecular Pharmacology U.S.A., vol. 19: 399, (1981). PA0 12. Conn et al, J. Biol. Chem. U.S.A., vol. 256: 1098, (1981). PA0 13. Conn et al, Endocrinology U.S.A., 109: 2040 (1981). PA0 14. Conn et al, Nature U.K. in press, 1982 "Conversion Of A Gonadotropin Releasing Hormone Antagonist To An Agonist: Implication For A Receptor Microaggregate As The Functional Unit for Signal Transduction." PA0 15. Conn et al, manuscript submitted, 1982 "Potency Enhancement of A GnRH Agonist: GnRH-Receptor Microaggregation Stimulates Gonadotropin Release."