EFFECTS OF BIM26226, A POTENT AND SPECIFIC BOMBESIN RECEPTOR ANTAGONIST, ON AMYLASE RELEASE AND BINDING OF BOMBESIN-LIKE PEPTIDES TO AR4-2J CELLS

Using AR4-2J rat pancreatic carcinoma cells, the effects of a novel bombesin (BN) receptor antagonist [D-F(5)Phe(6), D-Ala(11)]BN(6-13)OMe (BIM26226) on BN- or GRP-stimulated amylase release and binding of radio-labeled bombesin-like peptides to these cells were examined and compared to [D-Phe(6),Leu(13)Psi(CH2NH)Leu(14)]BN(6-14)(Psi Bn(6-14)), one of the most potent BN receptor antagonists presently known. BN and GRP both stimulated amylase release with EC(50) values in the nanomolar range. Both antagonists were devoid of agonist activity when tested alone. BIM26226 was most potent, antagonizing BN- or GRP-stimulated amylase release with IC50 values in the nanomolar range, whereas Psi Bn(6-14) was approximately ten times less potent. With I-125-[Tyr(15)]GRP bound to these cells, the binding affinities were BIM26226 > GRP > Psi Bn(6-14) much greater than neuromedin B. BIM 22626 was not able to inhibit binding of radio-labeled CCK-33, gastrin-17 or VIP. These results suggest that BIM26226 is one of the most potent and specific bombesin receptor antagonists in vitro and seems to be a useful tool to define the physiologic role of GRP in vivo.