Effect of a New Bombesin Receptor Antagonist, (E)-Alkene Bombesin Isostere, on Amylase Release from Rat Pancreatic Acini

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Abstract
The short-chain pseudopeptide, [d-Phe6, Leu13Φ(CH2NH)Leu14]bombesin(6–14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [d-Phe6, Leu13Φ[(E)CH = CH]Leu14] bombesin(6–14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 μM, and RBI showed slight agonistic activity at concentrations >10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC150 of 6.7 ± 1.7 nM, and induced almost-complete inhibition at 0.3 μM. RDI caused a dosedependent inhibition of amylase release, with an IC50 of 68.7 ± 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 μM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist. EABI was 10 times more potent than RDI in terms of inhibition of bombesin-stimulated amylase release. Thus, EABI can be a useful probe for studying the biological roles of bombesin and related peptides in a basic and clinical sense.

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