In vitro μ‐opioid receptor activation potential of U10 and β‐U10, positional isomers of the synthetic opioid naphthyl U‐47700

Abstract

New synthetic opioids (NSOs) with diverse chemical structures continue to appear on recreational drug markets worldwide. U‐type opioids have become one of the largest groups of non‐fentanyl‐related NSOs. Starting in 2020, a previously unreported U‐compound coined “β‐U10” (2‐naphthyl U‐47700; N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylnaphthalene‐2‐carboxamide) was identified in Australia and the United States. β‐U10 is a positional isomer of α‐U10 (1‐naphthyl U‐47700), more commonly known as “U10.” Here, the first comparative in vitro pharmacological characterization of naphthyl U‐47700 (U10 and β‐U10), together with the structural analogue U‐47700 and fentanyl, is reported. Application of a cell‐based μ‐opioid receptor (MOR) activation (β‐arrestin 2 recruitment) assay demonstrated β‐U10 (EC50 = 348 nM; Emax = 150% vs. hydromorphone) to be less potent than U‐47700 (EC50 = 116 nM; Emax = 154%) and fentanyl (EC50 = 9.35 nM; Emax = 146%) but considerably more active than the α‐isomer (EC50 value in the μM range). For the latter, maximum receptor activation could not be reached at 100 μM. The difference in MOR activation potential for U10 and β‐U10 stresses the importance of (analytical) differentiation between closely related analytes. The emergence of β‐U10 on the recreational drug market is an example of the continuing emergence of non‐fentanyl‐related NSOs and further emphasizes the need to closely monitor fluctuations in the drug supply.