The primary goals of this research are to obtain an understanding of the Chemical-physical basis for glucagonstructure-biological activity relationships, and the development of glucagon antagonist for potential use in the treatment of diabetes and related syndromes. We seek to utilize structure-activity insights tO develop glucagon analogues with high receptor specificity for glucagon receptors, especially analogues that can act as antagonists at the gluagon receptor. With these analogues and with the use of in vitro and in vivo assays and of the cloned glucagon receptor we seek to obtain a better understanding of the role Of glucagon in the control of glucose metabolism and blood glucose levels in the normal and diabetic state, and the mechanism(s) of glucagon action.
The specific aims related to these general goals are the following. To utilize conformational and topographical constraints and related structural modifications to obtaln more potent, stable and prolonged acting glucagon antagonists; to utilize newly designed assays and binding studies to examine structure-activity relationships of. glucagon, especially potent and prolonged acting antagonist analogues; to further develop the best synthetic and analytical methodology that will allow high yield synthesis of glucagon analogues; to further develop asymmetric synthesis methodology necessary for preparing unusual and novel amino acids and mimetics for incorporation into glucagon; to further examine the mechanisms of action of glucagon in normal and diabetic animals with special emphasis on in vivo studies using agonist and antagonists, and especially antagonists of diabetic ketoacidosis; to examine the conformation properties of glucagon analogues, especially analogues with exceptional agonist or antagonist biological activities; and to utilize homology modeling and computational chemistry, to examine the possible structure of the human glucagon receptor, and to examine the validity of the model by site specific mutagenesis of the glucagon receptor and ligand modification. Special emphasis will be placed on determining differences in how agonists and antagonists interact with glucagon receptors.
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