The primary goals of this research are to obtain an understanding of the chemical-physical basis for glucagon structure-biological activity relationships. We wish to utilize the insights from these studies to develop glucagon analogues with high receptor specificity for functionally different glucagon receptors, especially specific inhibitor (antagonists) of glucagon itself and of glucagon action. With these analogues we will seek to obtain a deeper understanding of the role of glucagon in the control of glucose metabolism and glucose levels in the normal and diabetic state, and the mechanisms of glucagon action. There is a need for a better understanding of glucose homeostasis and the mechanisms that control glucose levels.
The specific aims of this research, therefore, are the following. We will continue to develop the total synthesis approach to glucagon analogues so as to obtain more potent and prolonged acting glucagon analogues. Structural and conformational considerations, including conformational constraints, will be used to develop glucagon structure-biological activity relationships and to utilize these results to design more potent, prolonged acting, and receptor specific glucagon antagonist analogues. We seek to obtain receptor selective glucagon analogues that will help us to examine more precisely the multiple transduction mechanisms we have uncovered for glucagon action. Of special interest are those mechanisms which appear to be non-cAMP dependent processes. We will develop the synthetic, analytical, and preparative purification methods so that high yields of highly purified glucagon analogues can be obtained. The conformation properties of glucagon analogues, particularly those that are conformationally constrained and have unique biological properties, will be examined by biophysical methods, and the results utilized to develop a working model for glucagon conformation-biological activity relationships. Further examination of the mechanism(s) of glucagon activity will be made using the perifused liver slice system we recently developed including the effects on cAMP production, cAMP-dependent protein kinase, Ca+2 efflux and redistribution, glucose release, etc. As time permits we will further examine a lead we have for a somatostatin analogue that has high specificity for glucagon- release inhibition.
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