Novel C-terminal gastrin antagonists. Synthesis and biological activity.
The C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, is a full agonist of gastrin, but des-Phe analogues, including Boc-Trp-Met-Asp-NH2, are antagonists. To ascertain the minimum structural requirement for an antagonist, we used conventional solution phase methodology to synthesize analogues with further modifications including removal of the alpha-amino group of Trp, conversion of the indole to a phenyl ring, and methylation of amide bonds. These analogues were tested for their effect on pentagastrin-stimulated acid release in dogs surgically prepared with a gastric fistula. When infused intravenously at a dose of 20 pmol kg-1 h-1, the peptides significantly inhibited acid secretion. The extent of inhibition ranged from 12% to 60%. Thus, tripeptide analogues based on the C-terminal sequence of gastrin act as potent and specific antagonists of gastrin-stimulated acid secretion.
Yasui
A
A
Department of Biochemistry, Queen's University, Belfast, Ireland.
Douglas
A J
AJ
Walker
B
B
Magee
D F
DF
Murphy
R F
RF
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D005755:Gastrins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013758:Tetragastrin
D005755:Gastrins; D010446:Peptide Fragments; D013758:Tetragastrin