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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK021085-20A1
Application #
2540736
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Laughlin, Maren R
Project Start
1977-09-01
Project End
2001-03-31
Budget Start
1997-04-15
Budget End
1998-03-31
Support Year
20
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Arizona
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Ying, Jinfa; Ahn, Jung-Mo; Jacobsen, Neil E et al. (2003) NMR solution structure of the glucagon antagonist [desHis1, desPhe6, Glu9]glucagon amide in the presence of perdeuterated dodecylphosphocholine micelles. Biochemistry 42:2825-35
Ahn, J M; Gitu, P M; Medeiros, M et al. (2001) A new approach to search for the bioactive conformation of glucagon: positional cyclization scanning. J Med Chem 44:3109-16
Grieco, P; Gitu, P M; Hruby, V J (2001) Preparation of 'side-chain-to-side-chain' cyclic peptides by Allyl and Alloc strategy: potential for library synthesis. J Pept Res 57:250-6
Ahn, J M; Medeiros, M; Trivedi, D et al. (2001) Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4. J Pept Res 58:151-8
Ahn, J M; Medeiros, M; Trivedi, D et al. (2001) Development of potent truncated glucagon antagonists. J Med Chem 44:1372-9
Trivedi, D; Lin, Y; Ahn, J M et al. (2000) Design and synthesis of conformationally constrained glucagon analogues. J Med Chem 43:1714-22
Azizeh, B Y; Van Tine, B A; Trivedi, D et al. (1997) Pure glucagon antagonists: biological activities and cAMP accumulation using phosphodiesterase inhibitors. Peptides 18:633-41
Azizeh, B Y; Ahn, J M; Caspari, R et al. (1997) The role of phenylalanine at position 6 in glucagon's mechanism of biological action: multiple replacement analogues of glucagon. J Med Chem 40:2555-62
Van Tine, B A; Azizeh, B Y; Trivedi, D et al. (1996) Low level cyclic adenosine 3',5'-monophosphate accumulation analysis of [des-His1, des- Phe6, Glu9] glucagon-NH2 identifies glucagon antagonists from weak partial agonists/antagonists. Endocrinology 137:3316-22

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