Discriminative stimulus and antinociceptive effects of sixteen nitazene analogs in rodents

Analogs of the benzimidazole opioid compound, etonitazene, have appeared in the illicit drug market in an attempt to circumvent control of fentanyl analogs. This study examined behavioral effects of 16 nitazene analogs. The discriminative stimulus effects of morphine, fentanyl, butonitazene, clonitazene, N-desethyl isotonitazene, etonitazene, etodesnitazene, 5-methyl etodesnitazene, 5-aminoisotonitazene, isotodesnitazene, isotonitazene, N-piperydinyl etonitazene, N-piperidinyl isotonitazene, N-pyrrolidino etonitazene, N-pyrrolidino isotonitazene, N-pyrrolidino metonitazene, N-pyrrolidino protonitazene, and ethyleneoxynitazene were tested in male Sprague-Dawley rats trained to discriminate morphine from saline. Antinociception was tested using a warm-water tail-flick assay using male Swiss-Webster mice. All the nitazene test compounds fully substituted for the discriminative stimulus effects of morphine and the substitution was blocked by naltrexone. The potencies of the test compounds varied widely with five compounds being 3- to 5-fold more potent than fentanyl (ED₅₀ = 0.009 mg/kg), two compounds being roughly equipotent, and nine compounds being 2- to 170-fold less potent.

Similarly, all of nitazene test compounds produced full antinociceptive effects at 50 °C that were blocked by naltrexone. Seven compounds were 7- to 150-fold more potent than fentanyl (ED₅₀ = 0.058 mg/kg), four compounds were approximately equipotent, and five compounds were less 3- to 20-fold less potent. Antinociceptive time courses varied widely, with the duration of peak effects ranging from 15 to 90 min. All benzimidazole analogs tested produced opioid-like effects with a wide range of potencies and time courses. These compounds will likely have substantial liability for illicit use, whether on their own or as contaminants.