Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose

Study authors Grant Glatfelter, Donna Walther, Michael Baumann and Marthe Vandeputte

Featured Paper of the Month – February 2024

Published in Psychopharmacology by Grant Glatfelter and Michael Baumann et al. of the NIDA IRP Designer Drug Research Unit.

Summary

Novel synthetic opioids, such as 2-benzylbenzimidazoles or “nitazenes”, are infiltrating recreational drug markets worldwide. Here, we examined the pharmacology of a series of nitazene analogs, as compared to fentanyl and morphine. Our findings reveal that nitazenes are potent mu-opioid receptor agonists that induce opioid-like effects in mice. Importantly, we show that certain analogs (e.g., isotonitazene, etonitazene) are much more potent than fentanyl, portending serious risk of overdose and other adverse effects in humans who are exposed to the drugs.

Publication Information

Glatfelter, Grant C; Vandeputte, Marthe M; Chen, Li; Walther, Donna; Tsai, Meng-Hua M; Shi, Lei; Stove, Christophe P; Baumann, Michael H

Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose Journal Article

In: Psychopharmacology (Berl), vol. 240, no. 12, pp. 2573–2584, 2023, ISSN: 1432-2072.

Abstract | Links

@article{pmid37658878,

title = {Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose},

author = {Grant C Glatfelter and Marthe M Vandeputte and Li Chen and Donna Walther and Meng-Hua M Tsai and Lei Shi and Christophe P Stove and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/37658878/},

doi = {10.1007/s00213-023-06451-2},

issn = {1432-2072},

year  = {2023},

date = {2023-12-01},

urldate = {2023-12-01},

journal = {Psychopharmacology (Berl)},

volume = {240},

number = {12},

pages = {2573--2584},

abstract = {RATIONALE: Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl).nnOBJECTIVES: Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl).nnMETHODS AND RESULTS: Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in male mice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC = 30 pM, E = 103%) and across all in vivo endpoints (ED = 3-12 μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects.nnCONCLUSIONS: Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}