SYNTHESIS OF MODULATOR PHOSPHOLIPIDS

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Modulator is a cellular regulator of the glucocorticoid receptor mechanism and probably of other steroid receptor mechanisms. Its action is to prevent the activation and functioning of the receptor complex, and to stabilize the ligand-receptor interaction of the unactivated form. Elucidation of its absolute structure and preparation of derivatives which may be superactive, antagonists or tailor-made to specify its action on a specific receptor system has become extremely important. The modulator has been purified most recently, and its provisional structure determined by physical and chemical methods to be an ether-aminophospholipid. Since the mode of action of modulator may be the key to explaining the activation mechanism of the receptor-complex in the cell, it is vital to have reagent qualities of the compound (with well-defined chemical structure) to discover its mechanism of action. Development of new synthetic methods for the preparation of modulator ether-phospholipid is the main objective of this research project. We will design structurally modified phospholipid compounds that will be developed on the basis of experimentally determined requirements for modulating potency and specificity. The synthesis will utilize techniques recently developed in the principal investigator's laboratory. The synthetic compounds will be tested in the principal co-investigator's laboratory. The synthetic compounds will be used to determine the absolute structure of the modulator; to identify and assess the role of each structural component in the biological action of the modulator; and to design and develop agonists and antagonists. Radioactive modulator will be prepared to conduct direct binding studies and to begin to delineate its cellular degradation. In addition to gaining insight into the normal physiological functioning of the receptor-complexes, the results emerging from the program may open new possibilities for the preparation of chemotherapeutic agents acting at receptors, such as anti-estrogen receptors in breast cancer, and anti- androgen receptors in prostate cancer.