Characterization of pharmacological inhibition of the hERG potassium channel by nitazene opioids

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Nitazene opioids are ‘street’ drugs, many of which are substantially more potent than heroin. They are linked to respiratory depression, but other adverse effects have not been widely investigated. Machine learning models have predicted that several nitazenes may interact with a major drug anti-target, the hERG cardiac potassium channel. This study was conducted to evaluate effects on hERG of isotonitazene, protonitazene, etonitazene, metonitazene and the related piperadine benzimidazoline brorphine. hERG-expressing HEK293 cells were studied using automated patch clamp. Using a standard + 20 mV command (WT) hERG tail current (I hERG ) was acutely inhibited by all 5 compounds with IC 50 values between 0.5 µM (protonitazene) and 1.32 µM (isotonitazene). Inhibition showed voltage- and time-dependence consistent with gating-dependent block. The IC 50 values for I hERG inhibition for inactivation-attenuated (N588K) hERG were 3.3–5.1 fold those for WT for protonitazene and isotonitazene. Mutations at S5 and S6 aromatic residues (F557, Y652, F656) affected both compounds, with a particularly marked influence of F656A (13-fold WT IC 50 for isotonitazene and 73-fold for protonitazene). Neither isotonitazene nor protonitazene impaired hERG channel trafficking to the surface membrane. In silico docking and molecular dynamics simulations reproduced binding to canonical binding residues. Combining fentanyl with isotonitazene or protonitazene exacerbated block compared to each compound alone. Hypokalemia (1 mM [K + ] o ) increased the potency of isotonitazene but not protonitazene. In conclusion, hERG is a direct target for nitazene opioids.