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doi:10.22028/D291-41151
Titel: | Are the N-demethylated metabolites of U-47700 more active than their parent compound? In vitro μ-opioid receptor activation of N-desmethyl-U-47700 and N,N-bisdesmethyl-U-47700 |
VerfasserIn: | Nordmeier, Frederike Cannaert, Annelies Stove, Christophe P. Schmidt, Peter H. Meyer, Markus R. Schaefer, Nadine |
Sprache: | Englisch |
Titel: | Drug Testing and Analysis |
Bandnummer: | 14 (2022) |
Heft: | 4 |
Verlag/Plattform: | Wiley |
Erscheinungsjahr: | 2021 |
Freie Schlagwörter: | live cell-based reporter assay NanoLuc Binary Technology® new synthetic opioids U-47700 μ-opioid receptor |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Studies on the tissue distribution of the new synthetic opioid U-47700 and its main metabolite N-desmethyl-U-47700 revealed about sixfold higher metabolite concentrations in pig brain as compared with the parent compound. To better assess the toxic potential of this drug, the aim of this study was to assess the in vitro μ-opioid receptor (MOR) activation potential of the main metabolites of U-47700, Ndesmethyl-U-47700, and N,N-bisdesmethyl-U-47700, using a live cell-based reporter assay based on NanoLuc Binary Technology®. Cells stably expressing human MOR and β-arrestin 2 (βarr2), each fused via a flexible linker to two complementary inactive subunits of the nanoluciferase, were seeded on poly-D-lysine-coated 96-well plates and treated with N-desmethyl-U-47700, N,N-bisdesmethyl-U-47700, U-47700, or hydromorphone as reference standard. MOR activation results in functional complementation of the nanoluciferase, which can be assessed via luminescence monitoring. The potency of the metabolites is lower than that of U-47700 (EC50 of 186 nM for U-47700, 3770 nM for N-desmethyl-U-47700, and >5 μM for N,N-bisdesmethylU-47700). The maximal efficacy (Emax) observed (relative to hydromorphone, set arbitrarily at 100%) decreased from 183% to 127% and 39.2% for U-47700, N-desmethyl-U-47700, and N,N-bisdesmethyl-U-47700, respectively. Thus, the loss of one or two methyl groups reduced the MOR activation potential, which was more pronounced if both methyl groups were removed. It is thus anticipated that the impact on MOR exerted by the higher metabolite concentration in brain has only little—if any relevance for the strong toxic effects of U-47700. |
DOI der Erstveröffentlichung: | 10.1002/dta.3182 |
URL der Erstveröffentlichung: | https://doi.org/10.1002/dta.3182 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-411511 hdl:20.500.11880/36929 http://dx.doi.org/10.22028/D291-41151 |
ISSN: | 1942-7611 1942-7603 |
Datum des Eintrags: | 23-Nov-2023 |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Experimentelle und Klinische Pharmakologie und Toxikologie M - Rechtsmedizin |
Professur: | M - Prof. Dr. Markus Meyer M - Prof. Dr. Peter Schmidt |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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Drug Testing and Analysis - 2021 - Nordmeier - Are the N‐demethylated metabolites of U‐47700 more active than their parent.pdf | 2,86 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons