Nitazene opioids and the heart: Identification of a cardiac ion channel target for illicit nitazene opioids

Abstract

The growing use of nitazene synthetic opioids heralds a new phase of the opioid crisis. However, limited information exists on the toxic effects of these drugs, aside from a propensity for respiratory depression. With restricted research availability of nitazenes, we used machine-learning-based tools to evaluate five nitazene compounds' interaction potential with the hERG potassium channel, a key drug antitarget in the heart. All nitazenes were predicted to inhibit hERG with low μM IC₅₀ values. These findings indicate a potential for proarrhythmic hERG block by nitazene opioids, warranting detailed cardiac safety evaluations of these drugs.

Keywords: Etonitazene; Isotonitazene; Long QT; Metonitazene; Nitazene; Opioid; Protonitazene; QT interval; Torsades de pointes; hERG.

Graphical abstract

Fig. 1

Drug structures of isotonitazene and protonitazene and illustrative prediction of action potential (AP) prolongation for simulated hERG block by protonitazene. (A) Isotonitazene (Ai) and protonitazene (Aii) are both 6-nitro-2 benzylbenzimidazole members of the benzimidazole group of synthetic opioids. The PredhERG multiclass prediction that yielded predicted IC₅₀ values highlighted (in magenta) parts of each molecule predicted to contribute to hERG channel inhibition by these compounds. For both drugs, aromatic rings (including that in the benzimidazole moiety) were highlighted as likely contributors to hERG interaction. (B,C) Ventricular AP simulations were conducted in April 2024 using the “AP Predict” online cardiac electrophysiology simulator [18]. The O'Hara Rudy CiPA ventricular AP model was selected and a pIC₅₀ value for I_Kr of 5.904 (corresponding to an IC₅₀ of 1.25 μM) was entered (based on PredhERG protonitazene evaluation in Table 1). APs were elicited at 0.5, 1 and 2 Hz. (B) shows APs in control and at a concentration of 3.41 μM (at 1 Hz). (C) Extent of prolongation of APD₉₀ (ΔAPD₉₀ (%)) plotted against 5 protonitazene concentrations (0.1, 0.3, 1, 3 and 10 μM) at 3 frequencies (0.5, 1 and 2 Hz). The observed ΔAPD₉₀ (%) values ranged from 4.38 to 111.77 % at 1 Hz. These simulations assume selective drug activity against hERG/I_Kr. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Effects of I_Krinhibition by protonitazene on human atrial APs and ventricular tissue excitation. (Ai) Simulated human atrial APs using the Colman et al. [21] model in control and with 3.41 μM protonitazene (the drug's potency against I_Kr was the same as for Fig. 1). APs were elicited by suprathreshold stimuli at a basic cycle length of 1000 ms (1 Hz) (BCL = 1000 ms). (Aii) ΔAPD₉₀ (%) for atrial APs plotted against 5 protonitazene concentrations (0.1, 0.3, 1, 3 and 10 μM) at 3 frequencies (0.5, 1 and 2 Hz). (Bi,Bii) Frequency- (Bi) and concentration- (Bii) dependent effects of protonitazene on the conduction velocity computed from the ventricular strand model. Concentration used for Bi was 3.41 μM and stimulation frequency for Bii was 1 Hz. Note Y (CV) axis starts at 0.5 m/s not 0. (Biii-Biv) Illustration of effects of 1 μM protonitazene on the propagation of excitation waves (Biii) and inducibility (Biv) of uni-directional conduction block in response to a premature stimulus. The inducibility was measured by the width of the VW at the ENDO-MID junction of the 1D strand model [22]. The 1D strand model had a length of 15 mm, which was discretised by a spatial resolution of 0.15 mm, forming 100 nodes of cells.