ABSTRACT
The synthesis of analogs of the C-terminal tridecapeptide of gastrin is described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethylalcohol or with 2-phenylethylamine, or by replacing the peptide bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38, [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-psi(CH2NH)-Leu11]-HG-13-I 31 and [Trp10-psi(CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-psi(CH2NH)-Asp12]-HG-13-I 30 and [Leu11-psi (CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.
Subject(s)
Gastrins/biosynthesis , Gastric Acid/metabolism , Gastrins/chemistry , Humans , Peptide Biosynthesis , Receptors, Cholecystokinin/antagonists & inhibitorsABSTRACT
The synthesis of analogs of the C-terminal tridecapeptide of gastrin in described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethytalcohol or with 2-phenylethylamine, or by replacing the peptid bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38 [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-((CH2NH)-Leu11]-HG-13-I 31 and (Trp10-((CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-((CH2NH)-Asp12]-HG-13-I 30 and [Leu11-((CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.