Etonitat and its related opioid agonist benzimidazole were discovered in the late 1950s by a team of Swiss researchers working at the pharmaceutical company CIBA (now Novartis). One of the first compounds studied by the Swiss team was 1-(beta-diethylaminoethyl) -2-benzyl benzimidazole, which was found to have 10% of morphine's analgesic activity in rodent bioassometry. This finding encouraged the team to begin a comprehensive systematic study of 2-benzyl benzimidazole and to establish the structural-activity relationship for this new family of painkillers. Two general synthesis methods were developed to prepare these compounds.

The first method involves the condensation of o-phenylenediamine with phenylacetonitrile to form 2-benzylbenzimidazole. The benzimidazole is then alkylated with the desired 1-chloro-2-dialkyl aminoethane to form the final product. This particular method is most useful for preparing benzimidazole without substituents on the benzene ring

The most general synthesis [4] developed by the Swiss team first involves the alkylation of 2, 4-dinitrochlorobenzene with 1-amino-2-diethylaminoethane to form N-(β-diethylaminoethyl)-2, 4-dinitroaniline [aka: N'- (2, 4-dinitrophenyl) -n, n-diethyl-ethane-1, 2-diamine]. The 2-nitro substituents on 2, 4-dinitroaniline compounds are then selectively reduced to corresponding primary amines by using ammonium sulfide as reducing agent. Ammonium sulfide can form hydrogen sulfide gas in situ by adding a concentrated ammonium hydroxide solution and saturating it with the solution. An intermediate formed by the selective reduction of 2-nitro-substituent 2-(β-diethylaminoethyl aminoethyl) -5-nitroaniline, which then reacts with the iminoethyl ether hydrochloride of 4-ethoxy phenylacetonitrile (aka: p-ethoxy benzyl cyanide). Iminoether, 2-(4-ethoxy phenyl) -acetyliminoate ethyl ester hydrochloride, is prepared as a gas by dissolving 4-substituted benzyl cyanide in a mixture of anhydrous ethanol and chloroform, and then saturating the solution with anhydrous hydrogen chloride. The reaction between 2-(beta-dialkyl aminoalkyl amine) -5-nitroaniline and the hydrochloride of iminoethyl ether results in the formation of etonitrazine. The procedure is particularly suitable for the preparation of 4-, 5-, 6- and 7-nitrobenzimidazole. The selection of altered substituted iminoethers of phenylacetic acid can provide compounds with multiple substituents at the benzene 2-site

Many analogues are known, the only other notable compound derived from the original study in the 1950s is clonitacetone, which is much weaker than etonissini (about 3 times morphine). More recently, since around the end of 2018, a number of designer analogues have started to appear on the illegal market around the world, with the most prominent compounds being metronidazole, isonidazole and ettazine, but others continue to appear