Synthesis of pseudo-peptide analogues of the C-terminal tetrapeptide of gastrin and evaluation of their biological activity on acid secretion.
The syntheses of pseudo-tetrapeptides Boc-Trp-psi (CH2-NH)-Met-Asp-Phe-NH2 21 and Boc-Trp-Met-psi (CH2-NH)-Asp-Phe-NH2 20, representing the C-terminal tetrapeptide sequence of gastrin, in which amide bonds were replaced by CH2-NH bond, are described, as well as the syntheses of pseudo-peptide analogues Boc-Trp-psi (CH2-NH)-Nle-Asp-Phe-NH2 16, Boc-Trp-Nle-psi (CH2-NH)-Asp-Phe-NH2 11, and Boc-Trp-Nle-Asp-psi (CH2-NH)-Phe-NH2 5, in which the methionyl residue was replaced by a norleucyl residue. Pseudo-peptides 16 and 21, in which the amide bond between Trp and Met (or Nle) was substituted by a CH2-NH bond, stimulated gastric acid secretion in the rat in vivo. Pseudo-peptides 11 and 20, where the amide bond between Met (or Nle) and Asp was replaced by a CH2-NH bond, did not exhibit any activity on acid secretion in the rat in vivo but were potent inhibitors of pentagastrin-induced acid secretion. Peptides 11, 16, 20 and 21 all recognize the gastrin receptor on a mucosal cell preparation. Pseudo-peptide 5, in which the amide bond between Asp and Phe was replaced by a CH2-NH bond, was a less potent inhibitor of pentagastin-induced acid secretion and had a weaker affinity than the other pseudo-peptides.
D000595:Amino Acid Sequence; D000818:Animals; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects; D005755:Gastrins / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects; D011949:Receptors, Cholecystokinin; D013329:Structure-Activity Relationship; D013758:Tetragastrin / Q000031:analogs & derivatives / Q000494:pharmacology
D005755:Gastrins; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin