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dc.contributor.authorCassell, Robert J.
dc.contributor.authorSharma, Krishna K.
dc.contributor.authorSu, Hongyu
dc.contributor.authorCummins, Benjamin R.
dc.contributor.authorCui, Haoyue
dc.contributor.authorMores, Kendall L.
dc.contributor.authorBlaine, Arryn T.
dc.contributor.authorAltman, Ryan A.
dc.contributor.authorRijn, Richard M. van
dc.identifier.citationCassell, R. J., Sharma, K. K., Su, H., Cummins, B. R., Cui, H., Mores, K. L., Blaine, A. T., Altman, R. A., & van Rijn, R. M. (2019). The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors. Molecules (Basel, Switzerland), 24(24), 4542.
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstractAs tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) 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 δOR’s protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR 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 δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-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 δOR and µOR 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.en_US
dc.rights© 2019 by the authors.en_US
dc.subjectMu opioid receptoren_US
dc.subjectDelta opioid receptoren_US
dc.subjectBiased signalingen_US
dc.subjectPlasma stabilityen_US
dc.titleThe Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptorsen_US
kusw.kuauthorSharma, Krishna K.
kusw.kuauthorAltman, Ryan A.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 6/15/2020:

Journal: Molecules (ISSN: 1420-3049, ESSN: 1420-3049) RoMEO: This is a RoMEO green journal Listed in: DOAJ as an open access journal Author's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: green tick author can archive post-print (ie final draft post-refereeing) Publisher's Version/PDF: green tick author can archive publisher's version/PDF General Conditions: On open access repositories Publisher's version/PDF may be used Published source must be acknowledged Creative Commons Attribution License 4.0 Authors retain copyright Authors are encouraged to submit their published articles to institutional repositories
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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Except where otherwise noted, this item's license is described as: © 2019 by the authors.