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In 2019, we published three innovative quantitative structure-activity relationship models (QSAR) for predicting the affinity of mu-opioid receptor (µOR) ligands. The three different models were then combined to produce a consensus model used to explore the chemical landscape of 3000 virtual fentanyl-like structures, also generated by us by a theoretical scaffold-hopping approach to explore potential novel active substances and predict their activity. Interestingly, five years have passed, and some of the virtual predicted compounds have been identified/reported to e.g. the EU Early Warning System or the United Nations Office on Drugs and Crime, thus confirming our warning hypothesis that new emerging drugs from our screen would find way to the market.

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics. [Display omitted] • Structures of the human μOR bound to fentanyl, morphine, PZM21, TRV130, and SR17018 • Fentanyl occupies extra minor pocket around TM2 and TM3 beyond the morphine pocket • Reduced ligand interaction with TM6/7 attenuates arrestin activity of μOR ligands • Structure-based design of fentanyl analogs with reduced arrestin activities of μOR Seeing how fentanyl, morphine, and other agonists bind and activate the μOR-G i complex provides the basis for designing ligands with reduced arrestin signaling. [ABSTRACT FROM AUTHOR]

Compounds that activate only the G-protein signalling pathway represent an effective strategy for making safer opioids. In the present study, we report the design, synthesis and evaluation of two classes of novel PZM21 derivatives containing the benzothiophene ring and biphenyl ring group respectively as biased μ-opioid receptor (μOR) agonists. The new compound SWG-LX-33 showed potent μOR agonist activity and produced μOR-dependent analgesia. SWG-LX-33 does not activate the β-arrestin-2 signalling pathway in vitro even at high concentrations. Computational docking demonstrated the amino acid residue ASN150 to be critical for the weak efficacy and potency of μOR agonists in arrestin recruitment., (© 2022 Wiley-VCH GmbH.)

Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most common cancer in infancy. Our purpose was to investigate in vitro how cancer cell survival occurs in presence of morphine in undifferentiated and differentiated SHSY-5Y human neuroblastoma cultured cell line. Exposure of differentiated cells to morphine dose-dependently induced apoptosis in these cells through c-Jun N-terminal kinase (JNK)/caspase pathway. Otherwise, morphine induced activation for mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, caused positive regulation of cell survival in undifferentiated cells. Therefore, cell differentiation state bimodally affects the cellular regulation activity triggered by morphine in isolated cultured neuroblastoma cells raising concerns about the application of morphine to this type of cancer patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)