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Nonpeptide cholecystokinin-2 receptor agonists.
S B Kalindjian1, D J Dunstone, C M Low
1James Black Foundation, 68 Half Moon Lane, London SE24 9JE, UK. barret.kalindjian@kcl.ac.uk
Journal of Medicinal Chemistry
|April 21, 2001
Summary
N-methylation of CCK2 receptor antagonists unexpectedly converted them into agonists. This agonist activity was blocked by a known antagonist, suggesting a novel mechanism for CCK2 receptor modulation.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Molecular Modeling
Background:
- Exploration of cholecystokinin B (CCK2) receptor antagonists for potential therapeutic applications.
- Observation of unexpected pharmacological behavior in structurally modified CCK2 receptor antagonists.
Purpose of the Study:
- To investigate the structural modifications leading to altered CCK2 receptor activity.
- To characterize the agonist properties of N-methylated CCK2 receptor antagonists.
- To elucidate the molecular interactions underlying antagonist versus agonist behavior.
Main Methods:
- Synthesis and in vivo evaluation of N-methylated CCK2 receptor antagonists.
- In vitro assays to confirm and characterize agonist activity.
- Competitive binding studies using a reference CCK2 receptor antagonist (L-365,260).
- Molecular modeling to analyze ligand-receptor interactions.
Main Results:
- N-methylation of the indolic N-H in CCK2 receptor antagonists resulted in agonist activity.
- Agonist activity was confirmed in vitro and could be antagonized by L-365,260.
- A common theme of agonist behavior was observed across multiple modified compounds.
- Molecular modeling provided insights into structural differences driving antagonist vs. agonist profiles.
Conclusions:
- Simple N-methylation can transform potent CCK2 receptor antagonists into agonists.
- This structural modification reveals a novel mechanism for CCK2 receptor activation.
- Understanding these structure-activity relationships is crucial for designing selective CCK2 receptor modulators.