Synthesis and Biological Evaluation of Bombesin Constrained Analogues

Analogues of bombesin which incorporate dipeptide or turn mimetics have been synthesized. One of them (compound 11) containing a seven-membered lactam ring revealed a good affinity for GRP/BN receptors on rat pancreatic acini (K i value of 1.7 ± 0.4 nM) and on Swiss 3T3 cells (K i value of 1.0 ± 0.2...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2000-06, Vol.43 (12), p.2356-2361
Main Authors: Cristau, Michèle, Devin, Chantal, Oiry, Catherine, Chaloin, Olivier, Amblard, Muriel, Bernad, Nicole, Heitz, Annie, Fehrentz, Jean-Alain, Martinez, Jean
Format: Article
Language:English
Subjects:
3T3 Cells
Amylases - metabolism
Animals
Biological and medical sciences
Bombesin - analogs & derivatives
Bombesin - chemical synthesis
Bombesin - chemistry
Bombesin - pharmacology
Chemical Sciences
In Vitro Techniques
Male
Medical sciences
Mice
Molecular Mimicry
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - metabolism
Oligopeptides - pharmacology
Organic chemistry
Pancreas - drug effects
Pancreas - metabolism
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rats
Rats, Wistar
Receptors, Bombesin - agonists
Receptors, Bombesin - antagonists & inhibitors
Receptors, Bombesin - metabolism
Structure-Activity Relationship
Thymidine - metabolism
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Summary:Analogues of bombesin which incorporate dipeptide or turn mimetics have been synthesized. One of them (compound 11) containing a seven-membered lactam ring revealed a good affinity for GRP/BN receptors on rat pancreatic acini (K i value of 1.7 ± 0.4 nM) and on Swiss 3T3 cells (K i value of 1.0 ± 0.2 nM). On the basis of this observation, antagonists containing the same dipeptide mimic were obtained by modification of the C-terminal part of the bombesin analogues. The most potent constrained compounds (15 and 17) were able to antagonize 1 nM bombesin-stimulated amylase secretion from rat pancreatic acini with high potency (K i = 21 ± 3 and 3.3 ± 1.0 nM, respectively) and 10-7 M bombesin-stimulated [3H]thymidine incorporation into Swiss 3T3 cells (K i = 7.8 ± 2.0 and 0.5 ± 0.1 nM, respectively).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990942i