COMPARATIVE-STUDY OF IN-VITRO AND IN-VIVO ACTIVITIES OF BOMBESIN PSEUDOPEPTIDE ANALOGS MODIFIED ON THE C-TERMINAL DIPEPTIDE FRAGMENT

Analogs of bombesin in which the peptide bond between the two last ami no acid residues were replaced by a pseudopeptide bond mimicking the t ransition state analog were evaluated. These compounds were able to re cognize the bombesin receptor on isolated rat pancreatic acini with hi gh potency (Ki from 0.60 +/- 0.27 nM to 4.3 +/- 2.3 IliM). Although th ey were devoid of agonist activity, they were able to antagonize bombe sin-induced amylase secretion in this model, with potencies in accorda nce with their affinities (IC50 from 1.6 +/- 0.3 nM to 10.0 +/- 1.7 nM ). When tested in vivo in the anesthetized rat, these bombesin recepto r antagonists exhibited high potency in inhibiting bombesin-induced pa ncreatic secretion ln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)(2)]-CHOH- (CH2)(3)-CH3 JMV845, was among the most potent compounds with ED50 of 7.82 +/- 2.89 nM in inhibiting bombesin-induced protein secretion). Th e results of this study showed that replacing the peptide bond between the two last amino acid residues in bombesin by mimicking the transit ion state analog resulted in in vitro and in vivo potent bombesin rece ptor antagonists. (C) 1998 Elsevier Science Inc.