Elsevier

Peptides

Volume 19, Issue 1, 1998, Pages 57-63
Peptides

Article
Comparative Study of In Vitro and In Vivo Activities of Bombesin Pseudopeptide Analogs Modified on the C-Terminal Dipeptide Fragment

https://doi.org/10.1016/S0196-9781(97)00275-1Get rights and content

Abstract

Azay, J., C. Nagain, M. Llinares, C. Devin, J. A. Fehrentz, N. Bernad, C. Roze and J. Martinez. Comparative study of in vitro and vivo activities of bombesin pseudopeptide analogs modified on the C-terminal dipeptide fragment. Peptides 19(1) 57–63, 1998.—Analogs of bombesin in which the peptide bond between the two last amino acid residues were replaced by a pseudopeptide bond mimicking the transition state analog were evaluated. These compounds were able to recognize the bombesin receptor on isolated rat pancreatic acini with high potency (Ki from 0.60 ± 0.27 nM to 4.3 ± 2.3 nM). Although they were devoid of agonist activity, they were able to antagonize bombesin-induced amylase secretion in this model, with potencies in accordance 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 receptor antagonists exhibited high potency in inhibiting bombesin-induced pancreatic secretion (H-DPhe-Gln-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). The results of this study showed that replacing the peptide bond between the two last amino acid residues in bombesin by mimicking the transition state analog resulted in in vitro and in vivo potent bombesin receptor antagonists.

Section snippets

Method

Structural formula of the compounds used in this study are listed in Table 1. Bombesin and the different bombesin analogs were synthesized in our laboratory according to the method previously described 15, 16.

For in vitro experiments, compounds were dissolved in dimethylsulfoxide and dilutions were made. Final solutions did not contain more than 1% DMSO.

For in vivo experiments, all compounds were dissolved in dimethylsulfoxide and diluted with 0.9% NaCl, containing 0.3% bovine serum albumin

In Vitro Studies

Bombesin, compounds I, JMV 594, JMV 641, JMV 717, JMV 736 and JMV 845 were very potent in antagonizing the binding of 125I-GRP to rat pancreatic acini with Ki values ranging from 0.67 to 9.8 nM (Fig. 1, Table 2). As previously described, bombesin was able to dose-dependently stimulate enzyme secretion from rat pancreatic acini, inducing a maximal response at about 1 nM that plateaued at higher concentrations. In the same assay, none of the bombesin analogs exhibited a proper effect even when

Discussion

The present results indicate that analogs of the C-terminal nonapeptide of bombesin modified in their C-terminal dipeptide moiety led to potent bombesin receptor antagonists, both in vivo and in vitro. Introduction of a mimic of the transition state at the peptide bond between the two last residues (e.g., compounds JMV594, JMV641, JMV717, JMV736 and JMV845) resulted in very potent bombesin receptor antagonists. None of these analogs, including the model compound 1, stimulated neither in vitro

References (29)

  • Chariot, J.; Rozé, C. Détermination automatisée de très faibles concentrations de bicarbonates. Application au suc...
  • F Cuttitta et al.

    Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer

    Nature

    (1985)
  • J.D Gardner et al.

    Regulation of amylase release from dispersed pancreatic acinar cells

    J. Physiol.

    (1977)
  • R.T Jensen et al.

    Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells

    Proc. Natl. Acad. Sci. USA

    (1978)

    • Cited by (0)

    View full text
    Copyright © 1998 Elsevier Science Inc. All rights reserved.