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.
Showing the most recent 10 out of 14 publications
