EFFECT OF A NEW BOMBESIN RECEPTOR ANTAGONIST, (E)-ALKENE BOMBESIN ISOSTERE, ON AMYLASE RELEASE FROM RAT PANCREATIC ACINI

The short-chain pseudopeptide, [D-Phe(6), Leu(13)Psi(CH2NH)Leu(14)]bom besin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to th e investigation of biological actions of bombesin and its related pept ides. We recently synthesized (E)-alkene bombesin isostere by replacin g the peptide bond with an (E)-double bond: [o-Phe(6),Leu(13)Psi[(E) C H = CH]Leu(14)] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI show ed no agonistic activity at concentrations up to 1 mu M, and RBI showe d slight agonistic activity at concentrations >10 nM. EABI caused a do se-dependent inhibition of amylase release stimulated by 0.1 nM bombes in, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibi tion at 0.3 mu M. RDI caused a dose-dependent inhibition of amylase re lease, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and righ tward shift of the entire dose-response curve of bombesin-stimulated a mylase release, and the degree of the shift was dependent on the conce ntrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase re leases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin oc tapeptide (0.1 nM), carbachol(10 mu M), vasoactive intestinal peptide( 1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The r esults indicate that EABI is a potent and specific bombesin receptor a ntagonist. EABI was 10 times more potent than RDI in terms of inhibiti on of bombesin-stimulated amylase release. Thus, EABI can be a useful probe for studying the biological roles of bombesin and related peptid es in a basic and clinical sense.