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. ^{[3] [1]} Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine. ^{[4] [5] [6] [7] [8]} 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. ^[9]

In the early 2020s, the substances have been recognized as emerging drugs of abuse. ^{[10] [11] [12]} Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States beginning in 2019. ^[13] 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. ^[12] Nitazene analogs have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom ^[14] and New Zealand. ^[15]

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. ^{[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [ excessive citations ]}

A 2019 publication ^[27] has shown the possibility the previously assumed binding position of the benzimidazole class, ^[28] 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, 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. While compounds from this class are sometimes incorrectly referred to as "nitazene", ^[30] the 4 unsubstituted compound nitazene itself is of relatively low potency and has not been reported as a designer drug, with most cases of abuse and overdose linked to more potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.

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	14030-71-8
	Ethylene nitazene	hydrogen		15327525
	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	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
	Etomethazene	4-ethoxy	20	168310446	95293-25-7
	Etonitazene 5-trifluoromethyl analogue (Etotriflazene) [31]	4-ethoxy		21815908
	5-Trifluoromethyl isotodesnitazene	4-isopropoxy
	Etonitazene 5-cyano analogue (Etocyanazene) [32]	4-ethoxy		27268	15419-87-1
	Etonitazene 5-acetyl analogue (Etoacetazene) [33]	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 [34]	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) [35]	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 [36]	4-(2-fluoroethoxy)		172332078
	Trifluorometonitazene	4-trifluoromethoxy
	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
	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 [37]	3,4-methylenedioxy
	Ethyleneoxynitazene [38]	fused tetrahydrofuran

See also

• 25-NB
• Arylcyclohexylamine
• List of aminorex analogues
• List of benzodiazepines
• List of fentanyl analogues
• List of phenyltropanes
• Utopioid

References

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