Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N‐terminal d‐Trp or d‐Tpi

SINISA RADULOVIC, REN‐ZHI ‐Z CAI, PETER SERFOZO, KATE GROOT, TOMMIE W. REDDING, JACEK PINSKI, ANDREW V. SCHALLY

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the D forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13ψ(CH2NH)Leu14-bombesin(6-14) and Leu13ψ(CH2NH)Phe14-bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I-Tyr4-bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist D-Tpi6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3095) was slightly more potent in these assays than D-Trp6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3125). Nevertheless, D-Trp6,Leu13ψ(CH2NH)Phe14-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nM. Our work indicated that the substitution of D-Trp and D-Tpi at position 6 of the pseudononapeptide bombesin analogs (ψ13-14), in which the Met14 residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.

Original languageEnglish (US)
Pages (from-to)593-600
Number of pages8
JournalInternational journal of peptide and protein research
Volume38
Issue number6
DOIs
StatePublished - Dec 1991

Keywords

  • Swiss 3T3 cells
  • bombesin antagonist
  • gastrin releasing peptide
  • rat pancreatic acini
  • small cell lung carcinoma

ASJC Scopus subject areas

  • Biochemistry

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