Short chain bombesin pseudopeptides with poterat bosnbesin receptor antagonist activity in rat and guinea pig pancreatic acinar cells

A series of potent bombesin antagonists based on the reduced C-terminal peptide bond modification which in the past resulted in the first really potent antagonists are compared for effects on bombesm-stimulated amylase release from and binding to rat and guinea pig pancreatic acini. It was found that the original member of this series, [Leu¹³ψ (CH₂NH)Leu¹⁴]bombesin, displayed partial agonist activity with 11% efficacy in the rat. More recent analogues of this type which were found previously to be even more potent pure antagonists in the guinea pig pancreas or 3T3 cells, exhibited similarly higher binding affinity for rat acini but displayed even higher residual partial agonist activity in the rat. For instance, [D-Phe⁶,Leu¹³ψ(CH₂NH)Phe¹⁴]bombesin-(6-14) was one of the most potent bombesin antagonists known in the guinea pig and 3T3 cell systems but has 40% partial agonist activity in the rat. Several structural modification strategies were developed to remove rat partial agonist properties with retention of high antagonist potency in all systems tested. The most effective of these was the substitution of a Cl on the aromatic ring of the Phe residue (p-Cl-Phe, Cpa) in position 14 to give [D-Phe⁶,Leu¹³α(CH₂NH)Cpa¹⁴bombesin-(6-14). This had higher binding affinities for both rat and guinea pig pancreatic acini and was a pure antagonist on both cell types. Another effective method was alteration of the stereochemistry of the position 14 amino acid in [D-Phe⁶, Leu¹³α(CH₂NH)D-Phe¹⁴]bombesin-(6-14) which had somewhat lowered binding affinities but pure antagonist properties. [D-Phe^6,14]bombesin-(6-14) itself, however, was a strong full agonist in the rat and a partial agonist in the guinea pig. These results describe strategies which have given short chain bombesin pseudopeptides which are devoid of agonist activity and retain potent receptor antagonism in all tissues tested and thus should be more useful for in vivo studies.