A synthetic glycine-extended bombesin analogue interacts with the GRP/bombesin receptor

alpha-amidation of a peptide (which takes place from a glycine-extended pre cursor) is required to produce biologically active amidated hormones, such gastrin-releasing peptide (GRP)/Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly -His-Leu-Met-NH2 (bombesin). It was shown that glycine-extended gastrin med iates mitogenic effects on various cell lines by interacting with a specifi c receptor, different from the classical CCK1 or CCK2 receptors. On the bas is of this observation, we have extended the concept of obtaining active gl ycine-extended forms of others amidated peptides to produce new active anal ogues. In this study, we have tested the biological behaviour of a syntheti c analogue of the glycine-extended bombesin (para-hydroxy-phenyl-propionyl- Gln-Trp-Ala-Val-Gly-His-Leu-Met-Gly-OH or JMV-1458) on various in vitro mod els. We showed that compound JMV-1458 was able to inhibit specific (3-[I-12 5]iodotyrosyl(15)) GRP ([I-125]GRP) binding in rat pancreatic acini and in Swiss 3T3 cells with K-i values of approximately 10(-8) M. In isolated rat pancreatic acini, we found that JMV-1458 induced inositol phosphates produc tion and amylase secretion in a dose-dependent manner. In Swiss 3T3 cells, the glycine-extended bombesin analogue dose-dependently produced [H-3]thymi dine incorporation. By using potent GRP/bombesin receptor antagonists, we s howed that this synthetic glycine-extended bombesin analogue induces its bi ological activities via the classical GRP/bombesin receptor. (C) 2000 Elsev ier Science B.V. All rights reserved.