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

Using AR4-2J rat pancreatic carcinoma cells, the effects of a novel bo mbesin (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 radi o-labeled bombesin-like peptides to these cells were examined and comp ared 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 GR P both stimulated amylase release with EC(50) values in the nanomolar range. Both antagonists were devoid of agonist activity when tested al one. BIM26226 was most potent, antagonizing BN- or GRP-stimulated amyl ase 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 b ound to these cells, the binding affinities were BIM26226 > GRP > Psi Bn(6-14) much greater than neuromedin B. BIM 22626 was not able to inh ibit 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.