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

S. Radulovic, R. Z. Cai, P. Serfozo, K. Groot, T. W. Redding, J. Pinski, Andrew V Schally

Research output: Contribution to journalArticle

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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
Pages (from-to)593-600
Number of pages8
JournalInternational Journal of Peptide and Protein Research
Volume38
Issue number6
StatePublished - Dec 1 1991
Externally publishedYes

Fingerprint

Bombesin Receptors
Bombesin
Swiss 3T3 Cells
Amylases
Assays
Cells
Gastrin-Releasing Peptide
Small Cell Lung Carcinoma
Thymidine
Inhibitory Concentration 50
Rats
Substitution reactions
gastrin releasing peptide (14-27)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi. / Radulovic, S.; Cai, R. Z.; Serfozo, P.; Groot, K.; Redding, T. W.; Pinski, J.; Schally, Andrew V.

In: International Journal of Peptide and Protein Research, Vol. 38, No. 6, 01.12.1991, p. 593-600.

Research output: Contribution to journalArticle

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T1 - Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi

AU - Radulovic, S.

AU - Cai, R. Z.

AU - Serfozo, P.

AU - Groot, K.

AU - Redding, T. W.

AU - Pinski, J.

AU - Schally, Andrew V

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N2 - 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.

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