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Summary: Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, N-desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and N-desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but N-desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics.