The primary aim of this research is to obtain an understanding of the chemical-physical basis for glucagon structure-biological activity relationships with the goal of developing glucagon analogues and derivatives which can act as specific inhibitors (antagonists) of glucagon action. We will then utilize these glucagon antagonists to obtain a deeper understanding of the role of glucagon in the normal state and in diabetes mellitus. An ultimate goal of this research is the design, synthesis, and development of an orally active glucagon antagonist for use in the treatment of diabetes mellitus. Recently we have developed a number of glucagon inhibitors (antagonists), and have demonstrated that the most active one can dramatically lower blood glucose levels in diabetic animals. We propose to follow up on the structural, synthetic, chemical, and biological insights we have gained from these studies in several ways: 1) we will further examine the in vivo and in vitro biological activities of our glucagon antagonists; 2) develop further synthetic and semisynthetic methods to obtain more potent, longer acting glucagon antagonist analogues (including fragment analogues); 3) carefully examine conformational and dynamic properties of the glucagon agonist and antagonist analogues and structure-biological activity relationships of these analogues in several assay systems, and then utilize this data to design (and synthesize) more potent antagonists; 4) develop better analytical and preparative purification methods, especially high pressure liquid chromatography, for glucagon and its analogues and derivatives so that the purest possible synthetic and semisynthetic analogues can be obtained; 5) examine the properties of glucagon receptors including the effects of ions and co-factors on glucagon agonist and antagonist binding; and 6) continue collaborations on the potential use of glucagon antagonists for the treatment of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK021085-10
Application #
3226875
Study Section
Endocrinology Study Section (END)
Project Start
1977-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
10
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Arts and Sciences
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Vessey, Kirstan A; Lencses, Kathy A; Rushforth, David A et al. (2005) Glucagon receptor agonists and antagonists affect the growth of the chick eye: a role for glucagonergic regulation of emmetropization? Invest Ophthalmol Vis Sci 46:3922-31
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; 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
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
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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