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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, N‐desmethyl‐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 …