Research will continue on the development of somatostatin analogs with increased activities and selectivity for inhibition of glucagon, growth hormone, and gastric acid secretion. These compounds, as well as providing much insight inot mechanisms of action of SRIF, could have therapeutic calue in the treatment of diabetes mellitus, acromegaly, gastric ulcers, acute pancreatitis, and possibly certain hormone-dependent tumors. An additional aspect of this work, which hasassumed much greater importance with our recent discovery of the first peptide antagonist of somatostatin, is the investigation of the structutal features responsible for antagonist activity. The availability of an antagonist will help to elucidate the functions of endogenous somatostatin in controlling many physiological processes. It is also possible that selective antagonists can be developed which could act as specific pseudo-releasing factors for several important hormones. Synthesis of analogs will continue to be established solid-phase methods, except for the new short, cyclic antagonist peptides and isosteric peptide bond replacements where new synthetic routes have been established. Structure-activity studies on wach series will be based on our own 12-residue amidated structures, the short cyclic sidulfide analogs of Sandoz, and the short hexapeptide analogs developed by Merck. Both agonists and antagonists will be tested in vivo in the rat for their inhibitory of stimulatory effects on Nembutal-stimulated growth hormone release and insulin and glucagon levels present in hepatic protal blood samples. Additionally, potential antagonists can now be screened for inhibition of somatostain effects on GH in a newly developed in vitro pituitary cell system. These three hormones are measured by standard radioimmunoassay techniques. A collaborative arrangement has been made for examining analog effects on gastrin-stimulated gastric acid release in the cat. Basic studies on atrial natriuretic peptide effects on GH and SRIF release and SRIF effects in somatotroph cytoskeletal conformation are also discussed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK018370-12
Application #
3226001
Study Section
Endocrinology Study Section (END)
Project Start
1977-05-01
Project End
1991-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
12
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Tulane University
Department
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Hinke, Simon A; Gelling, Rick; Manhart, Susanne et al. (2003) Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP). Biol Chem 384:403-7
Chang, C H; Chey, W Y; Erway, B et al. (1998) Modulation of secretin release by neuropeptides in secretin-producing cells. Am J Physiol 275:G192-202
Gelling, R W; Coy, D H; Pederson, R A et al. (1997) GIP(6-30amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro. Regul Pept 69:151-4
Chang, C H; Chey, W Y; Braggins, L et al. (1996) Pituitary adenylate cyclase-activating polypeptide stimulates cholecystokinin secretion in STC-1 cells. Am J Physiol 271:G516-23
Gu, Z F; Pradhan, T K; Coy, D H et al. (1995) Interaction of galanin fragments with galanin receptors on isolated smooth muscle cells from guinea pig stomach: identification of a novel galanin receptor subtype. J Pharmacol Exp Ther 272:371-8
Chang, C H; Chey, W Y; Coy, D H et al. (1995) Galanin inhibits cholecystokinin secretion in STC-1 cells. Biochem Biophys Res Commun 216:20-5
Gu, Z F; Pradhan, T K; Coy, D H et al. (1994) Galanin-induced relaxation in gastric smooth muscle cells is mediated by cyclic AMP. Peptides 15:1425-30
Yagci, R V; Alptekin, N; Zacharia, S et al. (1991) Galanin inhibits pancreatic amylase secretion in the pentobarbital-anesthetized rat. Regul Pept 34:275-82
Rossowski, W J; Rossowski, T M; Zacharia, S et al. (1990) Galanin binding sites in rat gastric and jejunal smooth muscle membrane preparations. Peptides 11:333-8
Yagci, R V; Alptekin, N; Rossowski, W J et al. (1990) Inhibitory effect of galanin on basal and pentagastrin-stimulated gastric acid secretion in rats. Scand J Gastroenterol 25:853-8

Showing the most recent 10 out of 14 publications