Pharmacologic Characterization of Substituted Nitazenes at μ , κ , and Δ Opioid Receptors Suggests High Potential for Toxicity

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 389; no. 2; pp. 219 - 228
• Main Authors: Kozell, Laura B, Eshleman, Amy J, Wolfrum, Katherine M, Swanson, Tracy L, Bloom, Shelley H, Benware, Sheila, Schmachtenberg, Jennifer L, Schutzer, Kamryn A, Schutzer, William E, Janowsky, Aaron, Abbas, Atheir I
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.05.2024
• Subjects: Neuropharmacology
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.123.002052

The benzimidazole opioids (substituted nitazenes) are highly potent opiod receptor (MOR) agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core. Affinities were assessed using agonist radioligand binding assays at human , , and opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in CHO cells. Notably, for MOR binding, nine substituted nitazenes had significantly higher affinities than fentanyl including N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, and N-desethyl isotonitazene; 13 had subnanomolar affinities. Only metodesnitazene and flunitazene had significantly lower affinities than fentanyl. Affinities for the substituted nitazenes at KOR and DOR relative to MOR were 46- to 2580-fold and 180- to 1280-fold lower, respectively. Functional activities were assessed using [ S]GTP S binding assays. Four nitazenes had subnanomolar potencies at MOR: N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, N-pyrrilidino protonitazene and N-desethyl isotonitazene. Ten substituted nitazenes had significantly higher potencies than fentanyl. All tested nitazenes were full MOR agonists. Potencies at KOR and DOR relative to MOR were 7.3- to 7920-fold and 24- to 9400-fold lower, respectively. Thus, many of these compounds are high affinity/high potency MOR agonists with elevated potential to elicit toxicity and overdose at low doses. SIGNIFICANCE STATEMENT: Substituted nitazenes are a growing public health threat. Although the 19 nitazenes tested vary in their opioid receptor pharmacology, a number are very high affinity, high potency, and high efficacy compounds- higher than fentanyl. Their pharmacology suggests high potential for harm.