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Pept Sci (Hoboken). 2019 Jan;111(1). pii: e24078. doi: 10.1002/pep2.24078. Epub 2018 May 25.

Equipotent enantiomers of cyclic opioid peptides at μ opioid receptor.

Author information

1
Laboratory of Chemical Biology and Peptide Research, Montreal Clinical Research Institute, 110 Pine Ave. West, Montreal, Quebec, Canada H2W 1R7.
2
Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada H3C 3J7.

Abstract

Head-to-tail cyclized analogues 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) were synthesized and pharmacologically characterized in vitro. 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.

PMID:
30801053
PMCID:
PMC6383560
[Available on 2020-01-01]
DOI:
10.1002/pep2.24078

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