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Aniquinazoline B, a fungal natural product, activates the μ-opioid receptor

The development of new μ-opioid receptor (MOR) agonists without the undesirable side effects, such as addiction or respiratory depression, has been a difficult challenge over the years. In the search for new compounds, we screened our chemical database of over 40.000 substances and further assessed...

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Main Authors: Damiescu, Roxana (Author) , Elbadawi, Mohamed (Author) , Dawood, Mona (Author) , Klauck, Sabine (Author) , Bringmann, Gerhard (Author) , Efferth, Thomas (Author)
Format: Article (Journal)
Language:English
Published: 23 May 2024
In: ChemMedChem
Year: 2024, Volume: 19, Issue: 19, Pages: 1-12
ISSN:1860-7187
DOI:10.1002/cmdc.202400213
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/cmdc.202400213
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.202400213
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Author Notes:Roxana Damiescu, Mohamed Elbadawi, Mona Dawood, Sabine M. Klauck, Gerhard Bringmann, and Thomas Efferth
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Summary:The development of new μ-opioid receptor (MOR) agonists without the undesirable side effects, such as addiction or respiratory depression, has been a difficult challenge over the years. In the search for new compounds, we screened our chemical database of over 40.000 substances and further assessed the best 100 through molecular docking. We selected the top 10 compounds and evaluated them for their biological activity and potential to influence cyclic adenosine monophosphate (cAMP) levels. From the tested compounds, compound 7, called aniquinazoline B, belonging to the quinazolinone alkaloids class and isolated from the marine fungus Aspergillus nidulans, showed promising results, by inhibiting cAMP levels and in vitro binding to MOR, verified through microscale thermophoresis. Transcriptomic data investigation profiled the genes affected by compound 7 and discovered activation of different pathways compared to opioids. The western blot analysis revealed compound 7 as a balanced ligand, activating both p-ERK1/2 and β-arrestin1/2 pathways, showing this is a favorable candidate to be further tested.
Item Description:Online verfügbar: 23. Mai 2024, Artikelversion: 15. Juli 2024
Gesehen am 20.01.2025
Physical Description:Online Resource
ISSN:1860-7187
DOI:10.1002/cmdc.202400213

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