Abilities of some tryptophan and phenylalanine derivatives to inhibit gastric acid secretion

Benzotript (N-p-chlorobenzoyl-l-tryptophan) has been shown to be a receptor-antagonist in vivo and in vitro for peptides from the gastrin family. In the present study, we examine tryptophan, and some of its N- and C-acylated derivatives, as well as some phenylalanine derivatives, to show their ability to inhibit gastrin-induced acid secretion in the rat in vivo and to compete for the binding of [125I]-(Leu-15)-HG-17 to its cellular receptor on rabbit isolated gastric mucosal cells. N- and C- derivatives of tryptophan and phenylalanine were found to inhibit gastrin-induced acid secretion and binding of [125I]-(Leu-15)-HG-17 to its mucosal cell receptors. By either criterion, the relative antagonistic potencies of the compounds tested were: tert-butyloxycarbonyl-l-tryptophan-p-nitrophenylester ⋍ tert-butyloxycarbonyl-l-tryptophan-carbamoylmethylester > tert-butyloxycarbonyl-l-tryptophyl-l-methionyl-carbamoylmethylester ⋍ tert-butyloxycarbonyl-l-phenylalanine-carbamoylmethylester ⋍ tert-butyloxycarbonyl-l-tryptophyl-l-methionyl-amide > tert-butyloxycarbonyl-l-tryptophan > tert-butyloxycarbonyl-l-phenylalanine >benzyloxycarbonyl-l-tryptophan ⋍ benzotript, with minor differences between the in vivo and the in vitro experiments. These results demonstrate that both the nature of the amino acid residue and the N- and C- substitutions are important in determining antagonist activity and affinity for gastrin receptors.