Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi

Ren Zhi Cai, Sinisa Radulovic, Jacek Pinski, Attila Nagy, Tommie W. Redding, Donald B. Olsen, Andrew V Schally

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Seven new antagonists of bombesin (Bn)/gastrin-releasing peptide (GRP) containing C-terminal Trp or Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-carboxylic acid) in a reduced peptide bond were synthesized by solid phase methods and evaluated biologically. The reduced bond in four [Leu13ψ(CH2NH)Trp14]Bn(6-14) analogs was formed by reductive alkylation at the dipeptide stage. In the case of three [Leu13ψ(CH2N)Tpi14]Bn(6-14) analogs, the Trp dipeptide with reduced bond was reacted with formaldehyde to form the corresponding Tpi derivative. These Tpi-containing analogs have a new reduced bond which is structurally more constrained. Leu13ψ(CH2N)Tpi14 analogs inhibit [125I][Tyr4]bombesin binding to Swiss 3T3 cells with IC50 values of 2-4 nM, compared to 5-10 nM for Leu13ψ(CH2NH)Trp14 analogs. Leu13ψ(CH2N)Tpi14 analogs are also more potent than Leu13ψ(CH2NH)Trp14 analogs in growth inhibition studies using Swiss 3T3 cells. The two best bombesin antagonists of this series, [D-Trp6,Leu13ψ(CH2N)Tpi14]Bn(6-14) (RC-3415) and [Tpi6,Leu13ψ(CH2N)Tpi14]Bn(6-14) (RC-3440), inhibited GRP-stimulated growth of Swiss 3T3 cells with IC50 values less than 1 nM. RC-3440 was also active in vivo, suppressing GRP(14-27)-stimulated serum gastrin secretion in rats. Bombesin/GRP antagonists, such as RC-3440, containing the new reduced bond (CH2N) reported herein are very potent.

Original languageEnglish
Pages (from-to)267-271
Number of pages5
JournalPeptides
Volume13
Issue number2
DOIs
StatePublished - Jan 1 1992
Externally publishedYes

Fingerprint

Bombesin
Swiss 3T3 Cells
Gastrin-Releasing Peptide
Dipeptides
Inhibitory Concentration 50
Gastrins
Alkylation
Growth
Carboxylic Acids
Formaldehyde
Rats
Derivatives
Peptides

Keywords

  • Bombesin antagonist
  • New reduced bond Tpi
  • Pseudononapeptide
  • Solid phase synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

Cai, R. Z., Radulovic, S., Pinski, J., Nagy, A., Redding, T. W., Olsen, D. B., & Schally, A. V. (1992). Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi. Peptides, 13(2), 267-271. https://doi.org/10.1016/0196-9781(92)90107-E

Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi. / Cai, Ren Zhi; Radulovic, Sinisa; Pinski, Jacek; Nagy, Attila; Redding, Tommie W.; Olsen, Donald B.; Schally, Andrew V.

In: Peptides, Vol. 13, No. 2, 01.01.1992, p. 267-271.

Research output: Contribution to journalArticle

Cai, RZ, Radulovic, S, Pinski, J, Nagy, A, Redding, TW, Olsen, DB & Schally, AV 1992, 'Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi', Peptides, vol. 13, no. 2, pp. 267-271. https://doi.org/10.1016/0196-9781(92)90107-E
Cai RZ, Radulovic S, Pinski J, Nagy A, Redding TW, Olsen DB et al. Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi. Peptides. 1992 Jan 1;13(2):267-271. https://doi.org/10.1016/0196-9781(92)90107-E
Cai, Ren Zhi ; Radulovic, Sinisa ; Pinski, Jacek ; Nagy, Attila ; Redding, Tommie W. ; Olsen, Donald B. ; Schally, Andrew V. / Pseudononapeptide bombesin antagonists containing C-terminal Trp or Tpi. In: Peptides. 1992 ; Vol. 13, No. 2. pp. 267-271.
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