Phenethyl ester derivative analogues of the C-terminal tetrapeptide of gastrin as potent gastrin antagonists

: A series of phenethyl ester derivative analogues of the C-terminal tetrapeptide of gastrin, in which the phenylalanyl residue has been replaced by a phenethyl group and the peptide bond between aspartic acid and phenylalanine by an ester bond, were synthesized. None of these derivatives were able to stimulate gastric acid secretion in the anesthetized rat, whereas they inhibited gastrin-induced acid secretion with ED50 values between 0.02 and 1.5 mg/kg. Among these derivatives, Boc-beta Ala-Trp-Leu-Asp phenethyl ester (9) and Boc-beta Ala-Trp-Leu-Asp p-fluorophenethyl ester (16) were very potent in inhibiting gastrin-induced acid secretion. From these studies, the significant role of the C-terminal dipeptide of gastrin was pointed out. More particularly, the functional role of the phenylalanine through the C-terminal carboxamide and its binding role through its aromatic ring were demonstrated.