List of benzimidazole opioids

Benzimidazole opioids, also known as nitazenes, are a class of synthetic opioids with an unusual benzimidazole structure often referred to as "opioid New Psychoactive Substances", or "opioid NPS".[1][2] First synthesized in the 1950s by CIBA Pharmaceuticals as potential analgesic medications, several substances in the class have been identified, the best known being etonitazene.[1] Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine. While several substances in this class have found applications in research, they have never been used in clinical medicine due to their profound risk of respiratory depression and death.[3] In the early 2020s, the substance has been recognized as emerging drugs of abuse.[4][5][6] Isotonitazine was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States beginning in 2019.[7] Previously known nitazene analogs such as metonitazine and butonitazine, as well as novel nitazenes not previously patented, have since been discovered in toxicologic samples during forensic investigations.[6]

Structure-activity relationship

The structure-activity relationship of the drug class has been explored to a reasonable extent. The optimal substitution pattern is fairly tightly defined (i.e. N,N-diethyl on the amine nitrogen, 4-ethoxy on the benzyl ring and 5-nitro on the benzimidazole ring), but even derivatives incorporating only some of these features are still potent opioids. If a methyl or carboxamide group is added on the alpha carbon of the benzyl group, or the benzyl is replaced by 2-phenylethyl, compounds of similar activity are obtained. 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][19]

A 2019 publication[20] has shown the possibility the previously assumed binding position of the benzimidazole class,[21] acting as a semi-rigid fentanyl analogue may be incorrect. Based on a large scale analysis of known opioid receptor ligands a template was created through manual overlaying and alignment which has identified several mu-specific areas within the receptor. In this analysis, it is noted, etonitazene now more closely matches another, separate mu-specific region, sharing only a small area in common with the fentanyl class.

Abuse

In the UK, nitazene abuse emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a 6-month period.[22] Most of the deaths have occurred outside of 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.

Table of benzimidazole opioids

Chemical structure Drug name Ring substitution Analgesic potency (morphine = 1) PubChem CAS number
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
meta-Metonitazene 3-methoxy 2
Metonitazene 4-methoxy 100 53316366 14680-51-4
Metonitazepyne 4-methoxy
Metonitazepipne 4-methoxy
N-Desethylmetonitazene 4-methoxy
Metomethazene 4-methoxy
Dimetonitazene 3,4-dimethoxy 10 162623836
α-methyl-metonitazene 4-methoxy 50 162625089 806634-80-0
Metonitazene phenethyl homologue (Ethylene metonitazene) 4-methoxy 50
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
Etomethazene 4-ethoxy 20 168310446 95293-25-7
Etonitazene 5-trifluoromethyl analogue (Etotriflazene)[23] 4-ethoxy 21815908
Etonitazene 5-cyano analogue (Etocyanazene) [24] 4-ethoxy 27268 15419-87-1
Etonitazene 5-acetyl analogue (Etoacetazene) [25] 4-ethoxy 25957 13406-60-5
Etonitazene 5,6-dichloro analogue (Etodicloazene) 4-ethoxy
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 [26] 162623834 734496-28-7
Etonitazene morpholine analogue 4-ethoxy 2 162623685 805958-08-1
Etonitazene 6-nitro isomer (iso-etonitazene) [27] 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
Butonitazene 4-butoxy 5 156588955 95810-54-1
Isobutonitazene 4-isobutoxy
Secbutonitazene 4-secbutoxy
Etoetonitazene 4-ethoxyethoxy 50 162623504 806642-21-7
Flunitazene 4-fluoro 1 156588967 2728-91-8
Clonitazene 4-chloro 3 62528 3861-76-5
α-carboxamido-clonitazene 4-chloro 3
Bronitazene 4-bromo 5 162623726
Methylnitazene (Menitazene) 4-methyl 10 162623683 95282-00-1
Ethylnitazene (Enitazene) 4-ethyl 20 162623845
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
Methylthionitazene 4-methylthio 50 162623790 102471-37-4
Ethylthionitazene 4-ethylthio 30 162623931 102758-70-3
Etodesnitazene phenylthio analogue 4-ethoxy 1 21045
Etodesnitazene phenylthio / pyrrolidine analogue 4-ethoxy 2 19846499
Methylenedioxynitazene[28] 3,4-methylenedioxy
Tetrahydrofuranitazene (Ethyleneoxynitazene) [29] fused tetrahydrofuran

See also

References
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