Nitazenes
Nitazenes are a chemically defined class of substances derived from the parent compound nitazene. Nitazenes were developed in the second half of the 1950s by the Swiss Ciba AG as pain-relieving agents. They are important as centrally active, selective μ-opioid receptor agonists. The high potency of fentanyl (in humans) is matched by only a few nitazenes and surpassed by etonitazene and isotonitazene. Due to unacceptable side effects, nitazenes were never included in the pharmacopoeia of human or veterinary medicine. Since 2019, highly potent nitazenes have proliferated as ″new synthetic opioids″ in the North American and European narcotics markets and as such have become a formative component of the opioid epidemic in the United States. Overdoses of nitazene opioids have led to several hundred documented fatalities.
History
[edit]In the mid-1950s, the pharmaceutical research department of the Ciba AG discovered the (low) analgesic effect of 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).[1] Systematic derivatization of this parent compound in the course of structure-activity relationship investigations revealed an enhancement of activity by nitration of the 5-position. 4'-Methoxylated and ethoxylated compounds achieved potencies in the hot plate test that were previously unattained.[2] The thus discovered etonitazene is the most potent nitazene opioid known to date. The morphine-like mechanism of action was elucidated from the antagonizability of analgesia with allylnormorphine. In a human clinical trail two nitazenes (etonitazene and clonitazene) were investigated in 363 patients and the results were published in 1958.[3] The nitazenes were notable for their low therapeutic index, which precludes their marketability as pharmaceutical drugs. March 2019 marked the beginning of the spread of nitazene opioids in the drug scene. Isotonitazene was the first member of the substance class to be offered for sale on the darknet and forensically detected in overdose deaths in Switzerland and Canada.
Structure
[edit]
Nitazenes are benzimidazoles that are substituted with a diethylaminoethyl group at the 1-position, in the 2-position with a benzyl group and in the 5-position with a nitro group. Compounds nitrated in the 6-position are less effective, the 4- or 7-nitro isomers are not analgesically active. Analgesically active nitazenes are also often substituted in the para-position of the benzyl group, more rarely in the meta position. At the methylene linker, a methyl or an amide group is tolerated stereospecifically by the target receptor.[4][5] Nitazenes are structurally unrelated to other opioids.
Analysis
[edit]Since 2024, a immunoassay-based point-of-care testing in the form of test strips is available for the detection of nitazenes.[6] The drug sample is added to water and requires sufficient solubility for the test to be successful. The detection limit of the highly potent isotonitazene is given as 2000-3000 ng/mL. The test is of limited general applicability for non-nitazene benzimidazole opioids. Desnitazenes, for example, which are not substituted at the benzo structure portion, cannot be successfully tested by this method. According to the manufacturer, there is no cross-reactivity with frequently used adulterants such as acetaminophen, caffeine, diphenhydramine, other non-benzimidazole opioids (heroin, methadone, fentanyl) and common non-opioid drugs (xylazine, MDMA, cocaine, ketamine).[7]
Pharmacology
[edit]Metabolism
[edit]The metabolization of nitazenes is species-dependent. In humans, the main degradation pathways are N-deethylation and, in cases of 4'-ethers, O-dealkylation. The 4'-hydroxy compounds are eliminated more quickly via the urine due to higher hydrophilicity and are predominantly detectable in the urine.[8] CYP3A4 or CYP2C8 are likely to be involved in N-deethylation.[9] Reduction of the nitro group occurs extrahepatically, probably via bacteria of the intestinal flora. Bioconjugates are excreted as various O-glucuronides. The N3 oxide is a secondary metabolite in humans. The 4'-hydroxy compounds in urine and the N-deethyl compounds in blood serve as forensic biomarkers.[8]
References
[edit]- ^ Hunger A, Kebrle J, Rossi A, Hoffmann K (1957). "Synthesis of basic substituted, analgesically active benzimidazole derivatives". Experientia. 13 (10): 400–1. doi:10.1007/BF02161116. PMID 13473817.
- ^ Gross F, Turrian H (1957). "On benzimidazole derivatives with strong analgesic activity". Experientia. 13 (10): 401–3. doi:10.1007/BF02161117. PMID 13473818.
- ^ Bromig G (1958). "Über neue starkwirkende Analgetika und ihre klinische Erprobung". Klin Wochenschr. 36 (20): 960–963. doi:10.1007/BF01486702. PMID 13612082.
- ^ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazole derivatives and related heterocycles III. Synthesis of 1-aminoalkyl-2-nenzyl-nitro-benzimidazoles". Helvetica Chimica Acta. 43 (4): 1032–46. doi:10.1002/hlca.19600430412.
- ^ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazole derivatives and related heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]acetic acid esters and amides". Helvetica Chimica Acta. 43 (6): 1727–33. doi:10.1002/hlca.19600430634.
- ^ BTNX Harm Reduction, Nitazene Test Strip
- ^ De Vrieze LM, Stove CP, Vandeputte MM (2024). "Nitazene test strips: a laboratory evaluation". Harm Reduct J. 21 (1): 159. doi:10.1186/s12954-024-01078-8. PMC 11350930. PMID 39198843.
- ^ a b Taoussi O, Berardinelli D, Zaami S, Tavoletta F, Basile G, Kronstrand R, Auwärter V, Busardò FP, Carlier J (2024). "Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene". Arch Toxicol. 98 (7): 2101–2116. Bibcode:2024ArTox..98.2101T. doi:10.1007/s00204-024-03735-0. PMC 11169013. PMID 38582802.
- ^ Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT (2024). "Metabolism of highly potent synthetic opioid nitazene analogs: N-ethyl-N-(1-glucuronyloxyethyl) metabolite formation and degradation to N-desethyl metabolites during enzymatic hydrolysis". Drug Test Anal. 17 (2): 238–249. doi:10.1002/dta.3705. PMID 38679851.