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Structure-activity relationship studies on cholecystokinin: analogues with partial agonist activity
M C Galas1, M F Lignon, M Rodriguez
1Centre de Pharmacologie-Endocrinologie, Montpellier, France.
The American Journal of Physiology
|February 1, 1988
Summary
Synthesized cholecystokinin (CCK) analogues reveal the phenylalanine aromatic ring is key for CCK receptor binding in the brain and pancreas. The C-terminal amide is vital for rat pancreatic acini activity but not essential for pancreatic CCK receptor binding.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Cholecystokinin (CCK) plays a crucial role in physiological processes, including pancreatic enzyme secretion.
- Understanding CCK receptor interactions is vital for developing targeted therapeutics.
- Previous studies highlight the importance of the C-terminal region of CCK for its biological activity.
Purpose of the Study:
- To synthesize and characterize hepta- and octapeptide analogues of the C-terminal part of cholecystokinin.
- To investigate the role of the C-terminal phenylalanine residue and the primary amide function in CCK receptor binding and biological activity.
- To explore the differential effects of CCK analogues on pancreatic acini and brain CCK receptors.
Main Methods:
- Synthesis of modified hepta- and octapeptide analogues of cholecystokinin.
- Assay of amylase release from rat pancreatic acini to determine biological activity.
- Radioligand binding studies using 125I-BH-CCK-9 to assess binding affinity to CCK receptors on rat and guinea pig pancreatic acini and brain tissues.
Main Results:
- Synthesized CCK analogues fully stimulated amylase release from rat pancreatic acini without desensitization at supramaximal concentrations.
- A strong correlation was observed between the ability of CCK analogues to stimulate amylase release and inhibit 125I-BH-CCK-9 binding to pancreatic CCK receptors.
- CCK analogues demonstrated potent recognition of guinea pig brain CCK receptors, indicating conserved binding interactions.
Conclusions:
- The aromatic ring of phenylalanine is essential for binding to both pancreatic and brain CCK receptors.
- The C-terminal primary amide function is not critical for binding to pancreatic CCK receptors.
- The C-terminal primary amide is crucial for the biological activity of CCK analogues in rat pancreatic acini.