Functional selectivity of EM-2 analogs at the mu-opioid receptor
The mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated...
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| Format: | Article |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1133961/full |
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| author | Justyna Piekielna-Ciesielska Davide Malfacini Francine Medjiofack Djeujo Chantal Marconato Karol Wtorek Girolamo Calo’ Anna Janecka |
| author_facet | Justyna Piekielna-Ciesielska Davide Malfacini Francine Medjiofack Djeujo Chantal Marconato Karol Wtorek Girolamo Calo’ Anna Janecka |
| author_sort | Justyna Piekielna-Ciesielska |
| collection | DOAJ |
| description | The mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated through the G protein from the opioid-related side effects mediated by β-arrestin pathway. In an effort to identify such biased ligands, here we present a series of thirteen endomorphin-2 (EM-2) analogs with modifications in positions 1, 2, and/or 3. All obtained analogs behaved as mu receptor selective agonists in calcium mobilization assay carried out on cells expressing opioid receptors and chimeric G proteins. A Bioluminescence Resonance Energy Transfer (BRET) approach was employed to determine the ability of analogs to promote the interaction of the mu opioid receptor with G protein or β-arrestin 2. Nearly half of the developed analogs showed strong bias towards G protein, in addition four compounds were nearly inactive towards β-arrestin 2 recruitment while blocking the propensity of EM-2 to evoke mu-β-arrestin 2 interaction. The data presented here contribute to our understanding of EM-2 interaction with the mu opioid receptor and of the transductional propagation of the signal. In addition, the generation of potent and selective mu receptor agonists strongly biased towards G protein provides the scientific community with novel tools to investigate the in vivo consequences of biased agonism at this receptor. |
| first_indexed | 2024-04-10T07:27:03Z |
| format | Article |
| id | doaj.art-f4a1f2d1899345fa81adb58a5b44cd70 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T07:27:03Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f4a1f2d1899345fa81adb58a5b44cd702023-02-24T05:39:56ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-02-011410.3389/fphar.2023.11339611133961Functional selectivity of EM-2 analogs at the mu-opioid receptorJustyna Piekielna-Ciesielska0Davide Malfacini1Francine Medjiofack Djeujo2Chantal Marconato3Karol Wtorek4Girolamo Calo’5Anna Janecka6Department of Biomolecular Chemistry, Medical University of Lodz, Lodz, PolandDepartment of Pharmaceutical and Pharmacological Sciences, Section of Pharmacology, University of Padova, Padova, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, Section of Pharmacology, University of Padova, Padova, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, Section of Pharmacology, University of Padova, Padova, ItalyDepartment of Biomolecular Chemistry, Medical University of Lodz, Lodz, PolandDepartment of Pharmaceutical and Pharmacological Sciences, Section of Pharmacology, University of Padova, Padova, ItalyDepartment of Biomolecular Chemistry, Medical University of Lodz, Lodz, PolandThe mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated through the G protein from the opioid-related side effects mediated by β-arrestin pathway. In an effort to identify such biased ligands, here we present a series of thirteen endomorphin-2 (EM-2) analogs with modifications in positions 1, 2, and/or 3. All obtained analogs behaved as mu receptor selective agonists in calcium mobilization assay carried out on cells expressing opioid receptors and chimeric G proteins. A Bioluminescence Resonance Energy Transfer (BRET) approach was employed to determine the ability of analogs to promote the interaction of the mu opioid receptor with G protein or β-arrestin 2. Nearly half of the developed analogs showed strong bias towards G protein, in addition four compounds were nearly inactive towards β-arrestin 2 recruitment while blocking the propensity of EM-2 to evoke mu-β-arrestin 2 interaction. The data presented here contribute to our understanding of EM-2 interaction with the mu opioid receptor and of the transductional propagation of the signal. In addition, the generation of potent and selective mu receptor agonists strongly biased towards G protein provides the scientific community with novel tools to investigate the in vivo consequences of biased agonism at this receptor.https://www.frontiersin.org/articles/10.3389/fphar.2023.1133961/fullopioid receptorsG proteinβ-arrestin 2endomorphin-2 analogscalcium mobilization assayBRET assay |
| spellingShingle | Justyna Piekielna-Ciesielska Davide Malfacini Francine Medjiofack Djeujo Chantal Marconato Karol Wtorek Girolamo Calo’ Anna Janecka Functional selectivity of EM-2 analogs at the mu-opioid receptor Frontiers in Pharmacology opioid receptors G protein β-arrestin 2 endomorphin-2 analogs calcium mobilization assay BRET assay |
| title | Functional selectivity of EM-2 analogs at the mu-opioid receptor |
| title_full | Functional selectivity of EM-2 analogs at the mu-opioid receptor |
| title_fullStr | Functional selectivity of EM-2 analogs at the mu-opioid receptor |
| title_full_unstemmed | Functional selectivity of EM-2 analogs at the mu-opioid receptor |
| title_short | Functional selectivity of EM-2 analogs at the mu-opioid receptor |
| title_sort | functional selectivity of em 2 analogs at the mu opioid receptor |
| topic | opioid receptors G protein β-arrestin 2 endomorphin-2 analogs calcium mobilization assay BRET assay |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1133961/full |
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