List of benzimidazole opioids
From Wikipedia, the free encyclopedia
Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba AG. The most important subgroup are the nitazene opioids, which since 2019 have become increasingly widespread as narcotics in North America and Europe. Due to unacceptable side effects like respiratory depression, there is no medical use for benzimidazole opioids.[1]
History
In 1957, the pharmaceutical research department of Ciba AG published the discovery of the (low) analgesic effect of 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).[2] Shortly afterwards, the nitazenes were discovered in structure-activity relationship studies.[3][4]
Structure-activity relationship
Summarize
Perspective
The class of substances is defined chemically by the presence of the benzimidazole core structure and pharmacologically by opioid activity. The compounds are derived from the historical prototype 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). The replacement of the N,N-dialkylamino unit by pyrrolidinyl or piperidinyl, which is found in nitazepyne and nitazepipne compounds, falls into the spectrum of designer drugs. Substitution of the benzyl for thienylmethyl, pyridylmethyl, α-napthylmethyl or styryl has a potency-reducing effect.[5][6] Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > n-propyloxy > methoxy > methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5.[6] The replacement of benzimidazole with an indole has been known from studies conducted by Ciba AG since 1963.[7]
Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply.[8][9][10][11][12][13][14][15][16][17][18][excessive citations]
Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.[19][20][21][22][23]
Prevalence
In the early 2020s, the substances have been recognized as emerging drugs of abuse.[24][25] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States in March and April 2019.[26] Previously known nitazene analogs such as metonitazene and butonitazene, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations.[25] Nitazenes have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom[27] and New Zealand.[28]
In the UK, abuse of nitazene analogues emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a 6-month period.[29] Most of the deaths have occurred outside London, the source of supply is thought to be by post from laboratories in China and some of the deaths have been associated by the mislabelling of nitazenes as fentanyl. Most cases of abuse and overdose are linked to potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.
Table of benzimidazole opioids
| Structure | Name | Ring sub. | Analgesic potency (morphine = 1) | PubChem | CAS # |
|---|---|---|---|---|---|
|
Desnitazene (1-diethylaminoethyl-2-benzyl-benzimidazole) | hydrogen | 0.1 | 28787 | 17817-67-3 |
 |
Metodesnitazene (Metazene) | 4-methoxy | 1 | 26412 | 14030-77-4 1071546-40-1 (HCl) |
 |
Metodesnitazepyne | 4-methoxy | |||
 |
Etodesnitazene (Etazene) | 4-ethoxy | 70 | 149797386 | 14030-76-3 |
 |
Etodesnitazepyne | 4-ethoxy | 20 | 162623599 | |
 |
Etodesnitazepipne | 4-ethoxy | 10 | 162623611 | 102762-98-1 |
 |
Protodesnitazene | 4-(n-propoxy) | 10 | 157010653 | 805212-21-9 |
 |
Isotodesnitazene | 4-isopropoxy | ~75 | 162623708 | 2732926-27-9 |
 |
Nitazene | hydrogen | 2 | 15327524 | 14030-71-8 |
 |
Ethylene nitazene | hydrogen | 15327525 | 194537-85-4 | |
 |
meta-Metonitazene | 3-methoxy | 2 | 96168-49-9 | |
 |
Metonitazene | 4-methoxy | 100 | 53316366 | 14680-51-4 |
 |
Metonitazepyne | 4-methoxy | 3053113-16-6 | ||
 |
Metonitazepipne | 4-methoxy | |||
 |
N-Desethylmetonitazene | 4-methoxy | |||
 |
Metomethazene | 4-methoxy | 95138-58-2 | ||
 |
Dimetonitazene | 3,4-dimethoxy | 10 | 162623836 | 95809-33-9 |
 |
α-methyl-metonitazene | 4-methoxy | 50 | 162625089 | 806634-80-0 |
 |
α-methyl-etonitazene | 4-ethoxy | |||
 |
α-hydroxy-etonitazene | 4-ethoxy | 21815907 | ||
 |
Metonitazene phenethyl homologue (Ethylene metonitazene) | 4-methoxy | 50 | ||
 |
Ethylene etonitazene | 4-ethoxy | |||
 |
Etonitazene | 4-ethoxy | 1000-1500 | 13493 | 911-65-9 |
 |
O-Desethyl-etonitazene | 4-hydroxy | 1 | 156588969 | 94758-81-3 |
 |
N-Desethyletonitazene (NDE) | 4-ethoxy | 1000/1500-2000 | 162623580 | 2732926-26-8 |
 |
Etonitazene 5-amino metabolite | 4-ethoxy | 2 | 13408927 | 75821-80-6 |
 |
Etomethazene | 4-ethoxy | 20 | 168310446 | 95293-25-7 |
 |
Etonitazene 5-trifluoromethyl analogue (Etotriflazene)[30] | 4-ethoxy | 21815908 | 15451-92-0 | |
 |
5-Trifluoromethyl isotodesnitazene | 4-isopropoxy | 15451-92-0 | ||
 |
Etonitazene 5-cyano analogue (Etocyanazene) [31] | 4-ethoxy | 27268 | 15419-87-1 | |
 |
Etonitazene 5-acetyl analogue (Etoacetazene) [32] | 4-ethoxy | 25957 | 13406-60-5 | |
 |
Etonitazene 5,6-dichloro analogue (Etodicloazene) | 4-ethoxy | 102476-04-0 | ||
 |
Etonitazene N,N-dimethyl analogue | 4-ethoxy | 20 | 67089584 | 714190-52-0 |
 |
Etonitazepyne | 4-ethoxy | 180-190 | 155804760 | 2785346-75-8 |
 |
Etonitazepipne | 4-ethoxy | 190 [33] | 162623834 | 734496-28-7 |
 |
Etonitazene morpholine analogue | 4-ethoxy | 2 | 162623685 | 805958-08-1 |
 |
1-Ethyl pyrrolidinylmethyl N-desalkyl etonitazene | 4-ethoxy | |||
 |
Etonitazene 6-nitro isomer (iso-etonitazene) [34] | 4-ethoxy | 20 | 59799752 | 114160-61-1 |
 |
Protonitazene | 4-(n-propoxy) | 200 | 156589001 | 119276-01-6 95958-84-2 |
 |
Protonitazepyne | 4-(n-propoxy) | 180-190 | 168322728 | |
 |
Protonitazepipne | 4-(n-propoxy) | |||
 |
N-Desethylprotonitazene | 4-(n-propoxy) | |||
 |
Isotonitazene | 4-isopropoxy | 500 | 145721979 | 14188-81-9 |
 |
Isotonitazepyne | 4-isopropoxy | 168322631 | ||
 |
Isotonitazepipne | 4-isopropoxy | |||
 |
N-Desethylisotonitazene | 4-isopropoxy | 1000-2000 | 162623899 | 2732926-24-6 |
 |
iso-isotonitazene | 4-isopropoxy | |||
 |
Butonitazene | 4-butoxy | 5 | 156588955 | 95810-54-1 |
 |
Isobutonitazene | 4-isobutoxy | 168322282 | ||
 |
Secbutonitazene | 4-secbutoxy | 168322285 | ||
 |
Etoetonitazene | 4-ethoxyethoxy | 50 | 162623504 | 806642-21-7 |
 |
Fluornitrazene [35] | 4-(2-fluoroethoxy) | 172332078 | ||
 |
Trifluorometonitazene | 4-trifluoromethoxy | 954386-78-8 | ||
 |
Flunitazene | 4-fluoro | 1 | 156588967 | 2728-91-8 |
 |
Clonitazene | 4-chloro | 3 | 62528 | 3861-76-5 |
 |
Diclonitazene | 2,4-dichloro | |||
 |
α-carboxamido-clonitazene | 4-chloro | 3 | ||
 |
Bronitazene | 4-bromo | 5 | 162623726 | |
 |
Nitronitazene | 4-nitro | 101795-25-9 | ||
 |
Methylnitazene (Menitazene) | 4-methyl | 10 | 162623683 | 95282-00-1 |
 |
Ethylnitazene (Enitazene) | 4-ethyl | 20 | 162623845 | 114160-82-6 |
 |
Propylnitazene (Pronitazene) | 4-propyl | 50 | 162623877 | 700342-00-3 |
 |
t-Butylnitazene | 4-(tert-butyl) | 2 | 162623621 | 805215-64-9 |
 |
Acetoxynitazene | 4-acetoxy | 5 | 162623779 | 102760-24-7 |
 |
Methionitazene | 4-methylthio | 50 | 162623790 | 102471-37-4 |
 |
Ethylthionitazene | 4-ethylthio | 30 | 162623931 | 102758-70-3 |
 |
Etodesnitazene phenylthio analogue | 4-ethoxy | 1 | 21045 | 3275-92-1 |
 |
Etodesnitazene phenylthio / pyrrolidine analogue | 4-ethoxy | 2 | 19846499 | 13451-68-8 |
 |
Methylenedioxynitazene[36] | 3,4-methylenedioxy | |||
 |
Ethyleneoxynitazene[37] | fused tetrahydrofuran | |||
See also
References
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