Conformationally readdressed CCK-B/delta-opioid peptide ligands
G V Nikiforovich1, S A Kolodziej, B Nock
1Center for Molecular Design, Washington University, School of Medicine, St. Louis, MO 63130, USA.
Biopolymers
|October 1, 1995
Summary
Researchers modified cholecystokinin (CCK) peptides to create analogues that selectively bind to CCK-B or delta-opioid receptors. Minimal structural changes successfully redirected peptide interactions to a different receptor system.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Neuroscience
Background:
- Cholecystokinin (CCK) peptides play roles in various physiological processes.
- Modulating CCK receptor activity is a target for therapeutic interventions.
- Understanding peptide-receptor interactions is crucial for drug design.
Purpose of the Study:
- To design and synthesize novel peptide analogues with selective binding affinities.
- To investigate the structural modifications required for redirecting peptide interactions from CCK-B to delta-opioid receptors.
- To explore the potential of minimal chemical changes in altering peptide pharmacology.
Main Methods:
- Peptide synthesis of cyclic and linear analogues based on a CCK-related sequence.
- Molecular modeling to predict low-energy conformers and receptor compatibility.
- In vitro binding assays (Ki and IC50 values) to determine receptor selectivity.
Main Results:
- Cyclic analogue 1a demonstrated high affinity for delta-opioid receptors (Ki = 4.5 nM) and low affinity for mu-opioid receptors (>5000 nM).
- Analogue 1a showed selectivity for CCK-A receptors (IC50 = 1.6 nM) over CCK-B receptors (>10,000 nM).
- Minimal structural modifications, including cyclization and sulfur-to-methyl group replacement, altered receptor binding profiles.
Conclusions:
- It is possible to redirect peptide interactions from CCK-B receptors to delta-opioid receptors through subtle structural modifications.
- Conformational changes induced by minimal chemical alterations are key to achieving this receptor redirection.
- This strategy offers a novel approach for developing selective modulators of different receptor systems.
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