Benzimidazole opioids are a class of synthetic

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

s that contain a

benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...

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 Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

, there is no medical use for benzimidazole opioids.

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). Shortly afterwards, the

nitazene Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The analgesic, pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba Specialty Chemicals, Ciba ...

s were discovered in structure-activity relationship studies.

Structure-activity relationship

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,

pyridyl Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weakly alkaline, water-miscible liquid with a ...

methyl, α- napthylmethyl or styryl has a potency-reducing effect. Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > ''n''-propyloxy >

methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...

> methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5. The replacement of benzimidazole with an

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

has been known from studies conducted by Ciba AG since 1963. Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply. Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.

Prevalence

In the early 2020s, the substances have been recognized as emerging drugs of abuse.

Isotonitazene Isotonitazene is a synthetic opioid analgesic drug from the nitazene class and structural homolog of etonitazene, which has been sold as a designer drug. It has only around half the potency of etonitazene in animal studies, but it is likely eve ...

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. Previously known nitazene analogs such as

metonitazene Metonitazene is an analgesic compound related to etonitazene, which was first reported in 1957, and 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 t ...

and

butonitazene Butonitazene is a benzimidazole derivative with opioid effects, which has been sold over the internet as a designer drug. It has relatively low potency compared to many related compounds, and has generally been encountered as a component of mixtu ...

, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations. Nitazenes have been found in pills missold as other drugs, such as

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, in the United Kingdom and New Zealand. 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. 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 Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

. Most cases of abuse and overdose are linked to potent derivatives such as

protonitazene Protonitazene is a benzimidazole derivative with potent opioid effects which has been sold over the internet as a designer drug since 2019, and has been identified in various European countries, as well as Canada, the US and Australia. It has bee ...

isotonitazene Isotonitazene is a synthetic opioid analgesic drug from the nitazene class and structural homolog of etonitazene, which has been sold as a designer drug. It has only around half the potency of etonitazene in animal studies, but it is likely eve ...

etonitazepyne Etonitazepyne (''N''-pyrrolidino etonitazene) is a benzimidazole derivative with potent opioid effects which has been sold over the internet as a designer drug and linked to numerous cases of overdose. See also * Etazene * Etonitazene * Eton ...

, and

etodesnitazene Etodesnitazene (also known as desnitroetonitazene, etazen, etazene, and etazone) is a benzimidazole-derived opioid analgesic drug, which was originally developed in the late 1950s alongside etonitazene and a range of related derivatives. It is m ...

Table of benzimidazole opioids

References

{{Chemical classes of psychoactive drugs

Benzimidazole opioids Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The analgesic, pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba Specialty Chemicals, Ciba ...