Cyclic Opioid Peptides

Described in PeptideScience, researchers in the Peter Schiller Group, synthesized and pharmacologically characterized in vitro, head-to-tail cyclized analogs of the µ opioid receptor, MOR, agonist tetrapeptides DALDA (H‐Tyr‐D‐Arg‐Phe‐Lys‐NH2 and [Dmt1]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2; Dmt = 2′,6′-dimethyltyrosine) and their enantiomers, mirror-image isomers.

Three pairs of enantiomeric cyclic peptides with both mirror-image isomers having equipotent MOR binding affinities but different binding affinities at the δ and κ opioid receptors were identified. The cyclic peptide enantiomers c[‐D‐Arg‐Phe‐Lys‐Tyr‐] (1) and c[‐Arg‐D‐Phe‐D‐Lys‐D‐Tyr‐] (2), showed nearly identical MOR binding affinity (1-2 nM) and equipotent MOR antagonist activity. 

The results of a MOR docking study indicated a very similar binding mode of the two enantiomers with nearly complete spatial overlap of the peptide ring structures and side chain interactions with the same MOR residues. Compounds 1 and 2 represent the first pair of enantiomeric G-protein-coupled receptor, GPCR, ligands having multiple chiral centers, with both optical antipodes showing equal, low nanomolar receptor binding affinity.



Title:
Equipotent Enantiomers of Cyclic Opioid Peptides at μ Opioid Receptor
Authors:
Wenyi Li, Neil M. O'Brien‐Simpson, James A. Holden, Laszlo Otvos, Eric C. Reynolds, Frances Separovic, Mohammed Akhter Hossain, John D. Wade
Citation:
Peptide Science, Volume 110, Issue 3, Special Issue: Emerging Peptide Science in Australia, May 2018
URL:
https://onlinelibrary.wiley.com/doi/full/10.1002/pep2.24078

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