Hexobarbital

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates (such as Thiopental) have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

The chemical class of barbiturates are one of the oldest sedative-hypnotic agents known, dating back from the introduction of barbital in the early 20th century. In Hungary, hexobarbital (and other barbiturates) were regularly used as drugs by pregnant women attempting suicide. Hexobarbital was long thought to have potentially teratogenic and fetotoxic effects. The FDA has classified them as Pregnancy Category D or C. Some research however, indicate that ingestion of Hexobarbital might cause congenital abnormalities.

During World War II, Herta Oberheuser was a Nazi physician and convicted war criminal, investigating the effects of hexobarbital. The experiments were mostly performed on woman prisoners in the Ravensbrück concentration camp.

Hexobarbital is used as the narcotic in the Hexobarbital Sleep Test (HST). HST identifies rodents with high or low intensity of microsomal oxidation, so fast (FM) or slow metabolizers (SM). The sleep test is for example used to predict the susceptibility and resistance to post-traumatic stress disorder (PTSD) or to determine the effect of toxic compounds on sleep time.

Hexobarbital can be synthesized by reacting cyclohex-1-enyl 2-cyanopropanoate with guanidine and sodium methylate. A hexobarbital sodium intermediate is then formed which can be  methylated with dimethyl sulfate.

Another pathway for hexobarbital synthesis is reacting ethyl 2-cyano-2-(cyclohex-1-enyl)propanoate with N-methylurea. This reaction is done in two stages, in the first stage the reactants are added with tert-butylate in tert-butyl alcohol at 20-50 °C. In the second stage hydrogen chloride is added with ethanol and water as solvent.

One of the cytochrome P450 isozymes is coded by the gene CYP2B1, where hexobarbital is the substrate. Hexobarbital and the isozyme can form an enzyme-substrate-complex through a hydroxylation reaction, which is involved in the metabolism of xenobiotics. the concentration of hexobarbital also plays a role in oxygenase and oxidase activity of hepatic microsomal cytochrome P450.

Triacetyl oleandomycin, an inhibitor for isozyme CYP3A4, also inhibits hexobarbital metabolism and biological activity, indicating a close relationship between hexobarbital and cytochrome P450.