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dc.contributor.authorGach-Janczak, Katarzyna
dc.contributor.authorPiekielna-Ciesielska, Justyna
dc.contributor.authorAdamska-Bartłomiejczyk, Anna
dc.contributor.authorWtorek, Karol
dc.contributor.authorFerrari, Federica
dc.contributor.authorCalo', Girolamo
dc.contributor.authorSzymaszkiewicz, Agata
dc.contributor.authorPiasecka-Zelga, Joanna
dc.contributor.authorJanecka, Anna
dc.date.accessioned2018-12-04T09:35:10Z
dc.date.available2018-12-04T09:35:10Z
dc.date.issued2018-07
dc.identifier.citationPeptides 2018, 105:51-57en
dc.identifier.issn1873-5169
dc.identifier.pmid29684591
dc.identifier.doi10.1016/j.peptides.2018.04.014
dc.identifier.urihttp://hdl.handle.net/10146/618231
dc.description.abstractMorphine and related drugs, which are the most effective analgesics for the relief of severe pain, act through activating opioid receptors. The endogenous ligands of these receptors are opioid peptides which cannot be used as antinociceptive agents due to their low bioactivity and stability in biological fluids. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists in order to improve therapeutic utility of opioids. Analgesic effects of morphine are mediated mostly through activation of the mu opioid receptor. However, in the search for safer and more effective drug candidates, analogs with mixed opioid receptor profile gained a lot of interest. Recently, the concept of biased agonists able to differentially activate GPCR downstream pathways, became a new approach in the design of novel drug candidates. It is hypothesized that compounds promoting G-protein signaling may produce analgesia while β-arrestin recruitment may be responsible for opioid side effects. In this report we showed that replacement of the tyrosine residue in the mu-selective ligand Tyr-c[d-Lys-Phe-Asp]NH2 with 2',6'-dimethyltyrosine (Dmt) produced a cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH2 with mu/delta opioid receptor agonist profile. This analog showed improved antinociception in the hot-plate test, probably due to the simultaneous activation of mu and delta receptors but also significantly inhibited the gastrointestinal transit. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that this analog was a mu receptor agonist biased toward β-arrestin. β-Arrestin-dependent signaling is most likely responsible for the observed inhibition of gastrointestinal motility exerted by the novel cyclopeptide.
dc.description.sponsorshipThis work was supported by the Polpharma Scientific Foundation grant (11/XIII/2014 to KG) and grants from the Medical University of Lodz (No 503/1-156-02/503-11-002 and 502-03/1-156-02/502-14-301) and from the University of Ferrara (FAR grant to G.C.). KG is recipients of the Polish L’Oréal UNESCO Awards for Women in Science.en
dc.language.isoenen
dc.relation.urlhttps://www.sciencedirect.com/science/article/pii/S0196978118300883?via%3Dihuben
dc.rightsArchived with thanks to Peptidesen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectcyclic opioid peptidesen
dc.subjectBinding assayen
dc.subjectCalcium mobilization assayen
dc.subjectBioluminescence resonance energy transfer assayen
dc.subjectHot-plate testen
dc.subjectWhole gastrointestinal transit testen
dc.titleIn vitro and in vivo activity of cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH2, a mu opioid receptor agonist biased toward β-arrestin.en
dc.typeArticleen
dc.contributor.departmentNofer Institute of Occupational Medicineen
dc.identifier.journalPeptidesen
html.description.abstractMorphine and related drugs, which are the most effective analgesics for the relief of severe pain, act through activating opioid receptors. The endogenous ligands of these receptors are opioid peptides which cannot be used as antinociceptive agents due to their low bioactivity and stability in biological fluids. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists in order to improve therapeutic utility of opioids. Analgesic effects of morphine are mediated mostly through activation of the mu opioid receptor. However, in the search for safer and more effective drug candidates, analogs with mixed opioid receptor profile gained a lot of interest. Recently, the concept of biased agonists able to differentially activate GPCR downstream pathways, became a new approach in the design of novel drug candidates. It is hypothesized that compounds promoting G-protein signaling may produce analgesia while β-arrestin recruitment may be responsible for opioid side effects. In this report we showed that replacement of the tyrosine residue in the mu-selective ligand Tyr-c[d-Lys-Phe-Asp]NH2 with 2',6'-dimethyltyrosine (Dmt) produced a cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH2 with mu/delta opioid receptor agonist profile. This analog showed improved antinociception in the hot-plate test, probably due to the simultaneous activation of mu and delta receptors but also significantly inhibited the gastrointestinal transit. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that this analog was a mu receptor agonist biased toward β-arrestin. β-Arrestin-dependent signaling is most likely responsible for the observed inhibition of gastrointestinal motility exerted by the novel cyclopeptide.


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