Etonitazene

Etonitazene is a potent analgesic drug first reported in 1957 which has been shown to have approximately 1000–1500 times the potency of morphine in animal models, but only 60 times in man. It is one of several benzimidazole opioids, and is structurally related to clonitazene (where the p-ethoxybenzyl group is replaced by a p-chlorobenzyl group; however, clonitazene itself has only 3 times the potency of morphine). Etonitazene is a potent analgesic drug first reported in 1957 which has been shown to have approximately 1000–1500 times the potency of morphine in animal models, but only 60 times in man. It is one of several benzimidazole opioids, and is structurally related to clonitazene (where the p-ethoxybenzyl group is replaced by a p-chlorobenzyl group; however, clonitazene itself has only 3 times the potency of morphine). It has a strong dependency potential similar to that of morphine, and a strong tendency to produce respiratory depression, and is therefore not used in humans. It is however useful in addiction studies on animals. It is often used in studies requiring the animals to drink or ingest the opiate because it is not as bitter as the opiate salts, i.e., morphine sulfate. Illicit production and sale of etonitazene has been limited. This compound was identified on the illegal drug market in Moscow in 1998, appeared to have been illicitly manufactured, and was primarily smoked as pre-laced cigarettes. In another case a chemist at Morton Thiokol called Thomas K Highsmith produced the compound and placed it in a nasal inhaler. The drug was produced in Russia in 1996 and sold as 'Chinese Dwarf'. The drug resulted in an unconfirmed number of deaths simply because the potency in man wasn't known. It appears to have a steep dose-response curve making it particularly hazardous, more so than even fentanyl. If a carboxide moiety is placed onto the carbon between the benzimidazole and the p-ethoxybenzyl, compounds up to 4x more potent were discovered It is of interest that the extra hydrogen-bond acceptor overlays the nociceptin receptor such as MCOPPB. The most potent drug in this class is (S)-α-benzimidazoyl-(2)-α-phenylacetamide although more modern papers have proved that the class acts as a semi-rigid fentanyl analogue and rings other than benzene may yield even more potent compounds Of these analogues, only etonitazene and clonitazene are explicitly listed as illegal drugs under UN convention and so are illegal throughout the world. The rest would only be illegal in countries such as the US, Australia and New Zealand that have laws equivalent to the Federal Analog Act. In the United States it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9624 and a zero annual manufacturing quota as of 2013. Etonitazene has proved very important in mapping out the opiate receptor and some experimental compounds in which phenolic groupings have been replaced with nitro groupings have proved more active than the parent compound. Etonitazene and its related opioid agonist benzimidazoles were discovered in the late 1950s, by a team of Swiss researchers working at the pharmaceutical firm CIBA (now Novartis). One of the first compounds investigated by the Swiss team was 1-(β-diethylaminoethyl)-2-benzylbenzimidazole, which was found to possess 10% of the analgesic activity of morphine when tested in rodent bioassays. This finding encouraged the group to begin a comprehensive systematic study of 2-benzylbenzimidazoles and to establish the structure-activity relationship of this new family of analgesics. Two general synthetic methods were developed for the preparation of these compounds. The first method involved the condensation of o-phenylenediamine with phenylacetonitrile to form a 2-benzylbenzimidazole. The benzimidazole is then alkylated with the desired 1-chloro-2-dialkylaminoethane, forming the final product. This particular procedure was most useful for the preparation of benzimidazoles that lacked substituents on the benzene rings. A diagram of this method is displayed below.