Bioactivity Studies on New Gastrin Analogues

Abstract

Gastrin antagonists may be useful in the treatment of peptic ulcer disease and gastrointestinal malignancies. The aim of the present study was to synthesize gastrin analogues and test them for their ability to inhibit gastrin-stimulated acid secretion. Five peptides were synthesized: peptide [2], in which methionine was replaced by leucine, and the COOH-terminal amide was replaced by the thiomethylamide; peptide [3], in which the COOH-terminal phenylalanine was removed, and the aspartic acid thioamidated; peptide [5], in which methionine was replaced by leucine, and the peptide bond between leucine and aspartic acid was replaced by a thioamide; peptide [7], in which the bond between leucine and aspartic acid was replaced by a ketomethylene amino bond; and, finally, peptide [8], in which a β-bend was induced in the COOH-terminal region by the introduction of a D-phenylalanine in place of glycine. The biologic effect of the peptides was tested in the totally isolated, vascularly perfused rat stomach. The peptides were tested in concentrations of 10⁻-⁹, 10⁻-⁷, and 10⁻-⁵ M for agonist activity and together with gastrin 1–17, 5.2 ± 10⁻-¹⁰ M, at a concentration of 10⁻-⁵ M for antagonist activity. Peptide [2] had full biologic activity but greatly reduced potency, and peptide [7] had a faint biologic activity. None of the peptides showed any antagonist activity.

Key Words:

• Antagonists
• Bioactivity
• gastric secretion
• gastrin analogues
• synthetic peptides