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The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

Authors :
Richard M. van Rijn
Arryn T. Blaine
Benjamin R. Cummins
Ryan A. Altman
Krishna K. Sharma
Robert J. Cassell
Hongyu Su
Kendall L. Mores
Haoyue Cui
Source :
Molecules, Volume 24, Issue 24
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

As tool compounds to study cardiac ischemia, the endogenous &delta<br />opioid receptors (&delta<br />OR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the &delta<br />OR&rsquo<br />s protective role during ischemic events. Thus, a need remains for &delta<br />OR peptides with improved selectivity and unique signaling properties for investigating the specific roles for &delta<br />OR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to &delta<br />ORs and &micro<br />opioid receptors (&micro<br />ORs) and potency to inhibit cAMP signaling and to recruit &beta<br />arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the &delta<br />OR and &micro<br />OR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.

Details

Language :
English
Database :
OpenAIRE
Journal :
Molecules, Volume 24, Issue 24
Accession number :
edsair.doi.dedup.....addc6d89cd13daf29de127a199d1e068
Full Text :
https://doi.org/10.1101/750794