Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis.

Area of Science:

• Medicinal Chemistry
• Peptide Chemistry
• Pharmacology

Background:

• Dermorphin-derived cyclic tetrapeptides are potent mu and delta opioid receptor agonists.
• Disulfide bridges in peptides can be susceptible to metabolic degradation.

Purpose of the Study:

• To enhance the metabolic stability of dermorphin analogues by replacing the disulfide bridge with a bis-methylene moiety.
• To evaluate the impact of this structural modification on opioid receptor agonist activity.

Main Methods:

• Solid-phase synthesis of linear peptide precursors with allylglycine residues.
• Ring-closing metathesis to form olefinic peptides.
• Catalytic hydrogenation to yield saturated bis-methylene bridged peptides.
• In vitro opioid receptor binding and functional assays (guinea pig ileum, mouse vas deferens).

Main Results:

• Olefinic peptides exhibited reduced mu and delta opioid agonist potencies compared to parent cystine-containing peptides.
• The saturated bis-methylene bridged peptide with L-configuration was equipotent to its parent.
• The bis-methylene analogue with D-configuration was 10-27-fold less potent than its parent.
• Conformational analysis provided structural explanations for the observed changes in activity.

Conclusions:

• Replacing disulfide bridges with bis-methylene moieties can yield metabolically stable opioid peptide analogues.
• The stereochemistry at position 4 significantly influences the opioid activity of these modified peptides.
• Structural modifications impact peptide conformation and receptor interaction.