Metonitazene Chemical Properties

Boiling point:

571.8±45.0 °C(Predicted)

Density 

1.19±0.1 g/cm3(Predicted)

solubility 

DMF: 25 mg/ml; DMF:PBS (pH 7.2) (1:1): 0.5 mg/ml; DMSO: 20 mg/ml; Ethanol: 10 mg/ml

pka

9.90±0.25(Predicted)

InChI

InChI=1S/C21H26N4O3/c1-4-23(5-2)12-13-24-20-11-8-17(25(26)27)15-19(20)22-21(24)14-16-6-9-18(28-3)10-7-16/h6-11,15H,4-5,12-14H2,1-3H3

InChIKey

HNGZTLMRQTVPBH-UHFFFAOYSA-N

SMILES

C1(CC2=CC=C(OC)C=C2)N(CCN(CC)CC)C2=CC=C([N+]([O-])=O)C=C2N=1

Metonitazene Usage And Synthesis

Description

Metonitazene is an analgesic drug related to etonitazene and was first synthesized in the late 1950s by a Swiss chemical company in an effort to develop novel opioid alternatives to morphine. Metonitazene has been shown to have approximately 100 times the potency of morphine by central routes of administration, but if used orally it has been shown to have approximately 10 times the potency of morphine.

Chemical Properties

Metonitazene is classified as a novel opioid but is dissimilar from fentanyl and U-series analogues. This substance has been characterized as a white or off-white/beige powder, sometimes referred to as crystalline in consistency (Cayman Chemicals, 2020; Krotulski et al., 2021; PubChem, 2020). Both the free base and hydrochloride salt forms can appear as white or colored powders, while the citrate salt is described as a crystalline solid (Cayman, 2021a).

Physical properties

Metonitazene is lipophilic, as are its homologues etonitazene and isonitazene. The calculated octanol/water distribution coefficient for metonitazene is logP=3.734±0.936 at 25 °C. Metonitazene-free base has a solubility in dimethylformamide (DMF) of 25 mg/mL and of 20 mg/mL in dimethyl sulfoxide (DMSO). In a mixture of DMF and phosphate-buffered saline (PBS) DMF: PBS (pH 7.2) (1:1), the free base is soluble at 0.5 mg/mL and at 10 mg/mL in ethanol. Metonitazene citrate is soluble in DMF and DMSO at 10 mg/mL and 1 mg/mL in PBS (pH 7.2).

Uses

Metonitazene is an active analgesics with clinical applications.

Health effects

Metonitazene is considered a new psychoactive substance (NPS) and emerging potent synthetic opioid, causing increased public health concern beginning in 2020. Effects of Metonitazene are similar to other opioids and include pain relief, a sense of euphoria and sleepiness. It also causes vomiting and can slow respiratory rates, sometimes to dangerously low levels.

Biological Activity

Metonitazene (MTZ) is one of the newest non-fentanyl NSOs that has emerged in the illicit drug market followed by other analogues of nitazenes such as N-Piperidinyl etonitazene. MTZ, bearing a 4-methoxyphenyl group instead of the 4-isopropoxyphenyl moiety of ITZ, is internationally scheduled since June 2022. Metonitazene act as potent μ-opioid receptor agonist. MTZ is a high affinity ligand and potent MOR agonist at both native and recombinant MOR systems. It stimulate in vivo DA transmission in the NAc shell within a range of dosages able to reduce behavioral activity, and comparable with the concentration used for in vitro studies to determine affinity, potency and efficacy[6].

Toxicology

Metonitazene is a potent respiratory depressant in rabbits. A 10 μg/kg IV dose resulted in a 50% decrease in respiration frequency, equivalent to that caused by a 0.5 mg/kg dose of morphine. In mice, metonitazene’s acute intravenous toxicity (LD50) has been estimated at 50 mg/kg and 100mg/kg orally. In both preclinical and human studies, the effects of metonitazene could be antagonized by administration of nalorphine. This implies that the commonly available emergency intervention for opioid overdose, naloxone, should be effective as a reversal agent in cases of over-intoxication events where metonitazene is a contributing drug.

in vitro

In vitro studies of metonitazene’s activity at the mu-opioid receptor have found it to be between 113-121% that of fentanyl, and 184-340% that of hydromorphone. Not surprisingly, metonitazene produces robust typical mu-opioid receptor agonist pharmacodynamic effects.

References

1. Vandeputte, M.M., Van Uytfanghe, K., Layle, N.K., et al. Synthesis, chemical characterization, and μ-opioid receptor activity assessment of the emerging group of "nitazene" 2-benzylbenzimidazole synthetic opioids. ACS Chem. Neurosci. 12(7), 1241-1251 (2021). DOI:10.22541/AU.160520665.59016513/V2
2. Ujváry, I., Christie, R., Evans-Brown, M., et al. DARK classics in chemical neuroscience: Etonitazene and related benzimidazoles. ACS Chem. Neurosci. 12(7), 1072-1092 (2021). DOI:10.1021/acschemneuro.1c00037
3. Metonitazene in the United States-Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry DOI:10.1002/dta.3115
4. Pharmacological characterization of novel synthetic opioids: Isotonitazene, Metonitazene, and piperidylthiambutene as potent μ-opioid receptor agonists DOI:10.1016/j.neuropharm.2022.109263
5. https://www.overdosepreventionstrategies.org/glossary/metonitazene/
6 Luca M, et al. Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent μ-opioid receptor agonists. Neuropharmacology, 2022; 221: 109263.

Metonitazene(14680-51-4)Related Product Information

• Butonitazene
• Protonitazene hydrochloride