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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.

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


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.

[Available on 2020-01-01]

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