Aniquinazoline B, a Fungal Natural Product, Activates the μ‐Opioid Receptor

ChemMedChem
2024.0

Abstract

The development of new mu-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 beta-arrestin1/2 pathways, showing this is a favorable candidate to be further tested.The paper describes the discovery of a new mu-opioid receptor agonist, compound 7, from the marine fungus Aspergillus nidulans, through virtual screening. The binding to the receptor is confirmed in vitro by using microscale thermophoresis and cAMP inhibition. Further investigations are done through transcriptomics and western blot, generating a profile of the pathways affected by compound 7. image

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