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Gastrin releasing peptide antagonists with improved potency and stability
D C Heimbrook1, W S Saari, N L Balishin
1Department of Cancer Research, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Journal of Medicinal Chemistry
|July 1, 1991
Summary
Novel gastrin releasing peptide (GRP) antagonists were developed, showing high affinity for the GRP receptor and resistance to degradation. These compounds effectively blocked GRP-stimulated cell growth and hormone release.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Gastrin releasing peptide (GRP) is a peptide hormone homologous to bombesin.
- GRP plays a role in various physiological processes, including cell proliferation and hormone secretion.
Purpose of the Study:
- To develop novel GRP antagonists with enhanced stability and receptor affinity.
- To evaluate the efficacy of these antagonists in blocking GRP-mediated cellular responses.
Main Methods:
- C-terminal modification of N-acetyl-GRP-20-27 amide to create two series of GRP antagonists.
- Assays to determine receptor binding affinity (IC50), resistance to enzymatic degradation, and inhibition of GRP-stimulated mitogenesis.
- Measurement of intracellular calcium ([Ca2+]i) levels and gastrin release in vitro and in vivo.
Main Results:
- Two series of GRP antagonists were synthesized, exhibiting resistance to serum enzymatic degradation.
- Antagonists showed strong affinity for the GRP receptor, with IC50 values as low as 2 nM.
- All tested compounds blocked GRP-stimulated mitogenesis in mouse fibroblasts and GRP-induced [Ca2+]i elevation in human SCLC cells.
Conclusions:
- Novel C-terminally modified GRP antagonists are potent and stable inhibitors of GRP receptor activity.
- These antagonists effectively block GRP-mediated biological effects, including cell proliferation and hormone release.
- The developed antagonists represent promising therapeutic agents for GRP-related conditions.