The objective of the proposed research is to establish structural reasons for the general hormonal activity of thyroactive compounds and for the explicit endocrine mechanisms which mediate metabolic processes. It has been shown that the activity of the thyroid hormones and their metabolites depends primarily on the structure and relative orientations of the various moieties in the molecule. Studies of biological activity and receptor affinity data indicate unique structural requirements for activity and suggest stringent conformational preference for recognition by the receptor. The synthesis of efficient agonists and antagonists of thyroid hormone action is contingent upon a thorough understanding of intramolecular control of hormone conformation, the mechanism of conformational transmission, and the effects of specific substituents on the overall molecular shape. Only with a more detailed understanding of the nature of these hormones at the molecular level, which comes from the quantitative molecular details such as the distances between functional groups, their angular relationships, and the actual size and shape of the molecules, can a full understanding of their mechanisms of action be obtained. Such information can only be obtained from crystal and molecular structure determination. The information obtained from X-ray crystallographic determinations of appropriately chosen hormone analogues, precursors, and metabolites will be used in studies of solution spectral data, energy calculations, interpreting active site conformations, and determining structure-function relationships of hormone action. These studies will also unequivocally identify the stable conformational isomers of the thyroid hormones, delineate the differing degrees of flexibility possessed by the various isomers, and define the nature of long range interactions. These data are necessary for a full understanding of the basic mechanisms of thyroid hormone activity and biosynthesis and are a key to interpretation of their biochemical and physiological actions.