Chemistry:Hexobarbital

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Short description: Chemical compound
Hexobarbital
Hexobarbital.png
Hexobarbital ball-and-stick.png
Clinical data
Trade namesHexobarbital, Hexobarbitone, Methylhexabital, Methexenyl, Evipal
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding25%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC12H16N2O3
Molar mass236.271 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Density1.1623 g/cm3
Melting point146.5 °C (295.7 °F)
Boiling point378.73 °C (713.71 °F)
Solubility in water0.435 mg/mL (20 °C)
  (verify)

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.[1] It was also used to murder women prisoners at Ravensbrück concentration camp.[2] 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.[3] Hexobarbital is still used in some scientific research.[4]

History

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.[5] In Eastern Europe, hexobarbital (and other barbiturates) have been regularly used as drugs by pregnant women attempting suicide.[5] Hexobarbital was long thought to have potentially teratogenic and fetotoxic effects. The FDA has classified them as Pregnancy Category D or C.[6] Some research however, indicate that ingestion of Hexobarbital might cause congenital abnormalities.[5]

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.

Application in research

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 PTSD[7] or to determine the effect of toxic compounds on sleep time.[8][9]

Synthesis

Hexobarbital can be synthesised by reacting methyl (cyclohexen-1-yl) cyanoacetate with guanidine and sodium methylate. A hexobarbital sodium precursor is then formed which can be  methylated with dimethyl sulphate.[10]

Another pathway for hexobarbital synthesis is reacting methylcyclohexenylcyanoacetic acid ethyl ester with N-methylurea.[11] 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.

Synthesis of Hexobarbital by reacting methyl (cyclohexen-1-yl) cyanoacetate with guanidine and sodium ethylate, afterwards another methyl group is added through dimethyl sulphate
Alternative pathway for synthesis of Hexobarbital by reacting methylcyclohexenylcyanoacetic acid ethyl ester with N-methylurea.

Reactivity

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.[12]

Triacetyl oleandomycin, an inhibitor for isozyme CYP3A4, also inhibits hexobarbital metabolism and biological activity, indicating a close relationship between hexobarbital and cytochrome P450.[13]

Toxicity

Mechanism of actions

Molecular structure of S(+) and R(-) enantiomers of hexobarbital

The biological effects of hexobarbital depend primarily on its ability to penetrate the central nervous system.[14] Hexobarbital can potentiate GABAA receptors, like all barbiturates. It has been found over the years that the S(+) enantiomer of hexobarbital potentiates GABAA receptors more effectively than its R(-) enantiomer.[15] When GABA binds to the GABAA receptor, the chloride ion channels open such that chloride ions can flow into the neuron. This causes a hyperpolarization in the membrane potential of the neuron, which makes it less likely for the neuron to start an action potential. Therefore, this type of receptor is the major inhibitory neurotransmitter receptor in the mammalian central nervous system.[16] As a GABAA receptor potentiator, hexobarbital binds to the barbiturate binding site localized in the chloride ion channel, thereby increasing the binding of GABA and benzodiazepines to their respective binding site, allosterically.[17] Moreover, hexobarbital causes the chloride ion channel opening to their longest open state of 9 milli seconds, thereby causing the postsynaptic inhibitory effect to be extended.[15] In contrast to GABA, glutamate is the major excitatory neurotransmitter in the mammalian brain. In addition to the inhibitory effect, hexobarbital blocks, like all barbiturates, AMPA receptors, kainate receptors, neural acetylcholine receptors. And above all, barbiturates inhibit glutamate release by causing an open channel block on P/Q‐type high‐voltage activated calcium channels.[18] All in all, hexobarbital causes an CNS-depressant effect on the brain by inhibiting the glutamate release and potentiating the GABA-effect.

Metabolism

The hepatic metabolism of hexobarbital (HB) can be divided into different pathways all forming different metabolites.[19] The S(+) enantiomer of HB preferentially metabolizes into β-3'-hydroxyhexobarbital and the R(-) enantiomer preferentially metabolizes into α-3'-hydroxyhexobarbital, the reaction thus is stereoselective. Both enantiomers, however, form both α- and β-isomers. In total four enantiomers for 3'-hydroxyhexobarbital (3HHB) can be metabolized. This reaction is catalyzed by a cytochrome P450, CYP2B1.[20] All 3HHB isomers formed can undergo further metabolism via glucuronidation or dehydrogenation.

If 3HHB undergoes a glucuronidation reaction, via UDP-glucuronosyl transferases (UGTs), it is readily excreted. 3HHB can also undergo dehydrogenation, forming a reactive ketone, 3'-oxohexobarbital (3OHB). The biotransformation of 3HHB into 3OHB is via the enzyme 3HHB dehydrogenase (3HBD), a NAD(P)+ linked oxidation.[21] This enzyme is part of the aldo-keto reductase (AKR) superfamily. In humans, 3HBD has a high preference for NAD+.[20] These reactions are also stereospecific, the R(-) conformation preferentially forms 3OHB as 3HBD has the highest activity for this enantiomer in both alpha and beta form.[22]

New evidence proved the further metabolism of 3OHB into 1,5-dimethylbarbituric acid and a cyclohexenone glutathione adduct.[20] This biotransformation step takes place via an epoxide-diol mechanism.[23][24] The formation of a reactive epoxide, leads to the formation of the compounds mentioned.

Experiments in man indicated the major metabolites to be 3HHB, 3OHB and 1,5-dimethylbarbituric acid.[23]

Metabolic pathway of hexobarbital

Health effects in man

Excretion

The plasma half-life of HB in man is estimated at 222±54 min.[23] The clearance of HB differs between the two enantiomers and the age of the human subject. The clearance of the R(-) enantiomer is almost 10-fold greater than the clearance of the S(+) enantiomer. Clearance on average in elderly people, compared to young subjects, is slower.[25] Excretion is mainly via urine, for the three major metabolites.[20][23] The cyclohexenone glutathione adduct is excreted in the bile.[20]

Symptoms

An intoxication in man with hexobarbital can result in sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing and staggering. In some severe cases coma and death can be the result of an overdose.[19]

Effects on animals

The following table presents the studies about the effects of hexobarbital on animals, which are done in the 1900s. Most of these studies showed that hexobarbital has short-term toxicity effects and that it can induce hypnotic effects in mice, rabbits and frogs.

Table 1: Effects of hexobarbital on animals[26]
Organism Testtype Route Dose Effect Reference
rat LD50 intraperitoneal 330 mg/kg (330 mg/kg) [27]
rat LDLo subcutaneous 400 mg/kg (400 mg/kg) [28]
mouse LD50 oral 468 mg/kg (468 mg/kg) Prolongation of sleeping time [29]
mouse LD50 intraperitoneal 270 mg/kg (270 mg/kg) Prolongation of sleeping time and immobility time, which are potentiated by L-asparagine [30]
mouse LDLo subcutaneous 250 mg/kg (250 mg/kg) [31]
mouse LD50 intravenous 133 mg/kg (133 mg/kg) Behavioural: somnolence (general depressed activity) Archives Internationales de Pharmacodynamie et de Therapie., 163(11), 1966
mouse LDLo intrapleural 340 mg/kg (340 mg/kg) Hypnotic effect, which is potentiated by 4,5-dihydro-6-methyl-2[2-(4-pyridyl)-ethyl]-3-pyridazinone (U-320) [32]
mouse LD50 parenteral 160 mg/kg (160 mg/kg) Pharmacology and Toxicology.  English translation of FATOAO., 20(569), 1957
rabbit LDLo oral 1200 mg/kg (1200 mg/kg) Ultra-short actors; hypnotic effect

Minimal lethal dose: 1200 mg/kg

Minimal hypnotic dose: 15 mg/kg

[33]
rabbit LDLo intravenous 80 mg/kg (80 mg/kg) Ultra-short actors; hypnotic effect

Minimal lethal dose: 80 mg/kg

Minimal hypnotic dose: 15 mg/kg

[33]
rabbit LDLo rectal 175 mg/kg (175 mg/kg) Ultra-short actors; hypnotic effect

Minimal lethal dose: 175 mg/kg

Minimal hypnotic dose: 15 mg/kg

[33]
frog LDLo intraperitoneal 30 mg/kg (30 mg/kg) [34]
frog LD50 parenteral 148 mg/kg (148 mg/kg) Pharmacology and Toxicology.  English translation of FATOAO., 20(569), 1957

In popular culture

In Agatha Christie's 1937 mystery Cards on the Table, Hexobarbital is used in conjunction with Veronal to induce overdose. It is referred to by Hercule Poirot as both N-methyl-cyclo-hexenyl-methyl-malonyl urea and Evipan.[35]

References

  1. ↑ Lexikon der Neurowissenschaft: Hexobarbital (in German)
  2. ↑ Helm, Sarah (2015). If this is a woman: Inside Ravensbruck: Hitler's concentration camp for women. London: Abacus. pp. 243–258. ISBN 9780349120034. 
  3. ↑ Pubchem. "Hexobarbital | C12H16N2O3 - PubChem". https://pubchem.ncbi.nlm.nih.gov/compound/Hexobarbital#section=Chemical-Vendors. 
  4. ↑ "Duration of hexobarbital-induced sleep and monoamine oxidase activities in rat brain: Focus on the behavioral activity and on the free-radical oxidation". General Physiology and Biophysics 35 (2): 175–83. April 2016. doi:10.4149/gpb_2015039. PMID 26689857. 
  5. ↑ 5.0 5.1 5.2 "A study of the teratogenic and fetotoxic effects of large doses of barbital, hexobarbital and butobarbital used for suicide attempts by pregnant women". Toxicology and Industrial Health 24 (1–2): 109–19. 2008-02-01. doi:10.1177/0748233708089004. PMID 18818187. Bibcode: 2008ToxIH..24..109T. 
  6. ↑ "FDA Pregnancy Categories - CHEMM". https://chemm.nlm.nih.gov/pregnancycategories.htm. 
  7. ↑ "Hexobarbital Sleep Test for Predicting the Susceptibility or Resistance to Experimental Posttraumatic Stress Disorder". International Journal of Molecular Sciences 21 (16): 5900. August 2020. doi:10.3390/ijms21165900. PMID 32824478. 
  8. ↑ "Effect of cannabidiol on cytochrome P-450 and hexobarbital sleep time". Biochemical Pharmacology 30 (5): 503–7. March 1981. doi:10.1016/0006-2952(81)90636-5. PMID 7225146. 
  9. ↑ "Cadmium-induced potentiation of hexobarbital sleep time in rats". Experientia 30 (5): 528–9. May 1974. doi:10.1007/BF01926332. PMID 4833683. 
  10. ↑ VCH Publishers (2002). Ullman's encyclopedia of industrial chemistry.. Wiley-VCH. OCLC 50618230. http://worldcat.org/oclc/50618230. 
  11. ↑ Chumakova L, Patron A, Priest C, Karanewsky D, Kimmich R, Clayton B, Jeffrey B, Hammaker R, Chumakov V, Zhao W, Noncovich A, Ung J, "Compounds useful as modulators of trpm8", US patent 2015376136, published 31 December 2015, issued 12 December 2017, assigned to Senomyx Inc
  12. ↑ "Hexobarbital-binding, hydroxylation and hexobarbital-dependent hydrogen peroxide production in hepatic microsomes of guinea pig, rat and rabbit". Naunyn-Schmiedeberg's Archives of Pharmacology 314 (2): 201–10. November 1980. doi:10.1007/BF00504539. PMID 7453835. 
  13. ↑ Principles of biochemical toxicology. Informa Healthcare. 2009. pp. 181. ISBN 978-0-8493-7302-2. OCLC 243818515. 
  14. ↑ "Structural specificity of barbiturates and related drugs". Anesthesiology 57 (4): 314–20. October 1982. doi:10.1097/00000542-198210000-00014. PMID 6751157. 
  15. ↑ 15.0 15.1 "Anesthetics and ion channels: molecular models and sites of action". Annual Review of Pharmacology and Toxicology 41 (1): 23–51. 2001-04-01. doi:10.1146/annurev.pharmtox.41.1.23. PMID 11264449. 
  16. ↑ "Structure, function, and modulation of GABA(A) receptors". The Journal of Biological Chemistry 287 (48): 40224–31. November 2012. doi:10.1074/jbc.R112.386664. PMID 23038269. 
  17. ↑ "Allosteric actions of central nervous system depressants including anesthetics on subtypes of the inhibitory gamma-aminobutyric acidA receptor-chloride channel complex". Annals of the New York Academy of Sciences 625: 145–54. 1991. doi:10.1111/j.1749-6632.1991.tb33838.x. PMID 1711804. 
  18. ↑ "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia 53 Suppl 8 (s8): 12–25. December 2012. doi:10.1111/epi.12025. PMID 23205959. 
  19. ↑ 19.0 19.1 "Hexobarbital". https://go.drugbank.com/drugs/DB01355. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 "[New aspects of hexobarbital metabolism: stereoselective metabolism, new metabolic pathway via GSH conjugation, and 3-hydroxyhexobarbital dehydrogenases"]. Yakugaku Zasshi 124 (12): 857–71. December 2004. doi:10.1248/yakushi.124.857. PMID 15577260. https://www.jstage.jst.go.jp/article/yakushi/124/12/124_12_857/_pdf/-char/ja. 
  21. ↑ "Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D₂, and other endogenous and xenobiotic carbonyl compounds". Biochemical Pharmacology 86 (9): 1366–75. November 2013. doi:10.1016/j.bcp.2013.08.024. PMID 23994167. 
  22. ↑ "Stereoselective metabolism of the enantiomers of hexobarbital". The Journal of Pharmacology and Experimental Therapeutics 169 (2): 153–8. October 1969. PMID 5824599. https://jpet.aspetjournals.org/content/169/2/153. 
  23. ↑ 23.0 23.1 23.2 23.3 "Disposition of hexobarbitone in healthy man: kinetics of parent drug and metabolites following oral administration". British Journal of Clinical Pharmacology 15 (4): 459–64. April 1983. doi:10.1111/j.1365-2125.1983.tb01530.x. PMID 6849782. 
  24. ↑ "Hexobarbital metabolism: a new metabolic pathway to produce 1,5-dimethylbarbituric acid and cyclohexenone-glutathione adduct via 3'-oxohexobarbital". Xenobiotica; the Fate of Foreign Compounds in Biological Systems 23 (8): 925–34. August 1993. doi:10.3109/00498259309059419. PMID 8284947. 
  25. ↑ "Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin". British Journal of Clinical Pharmacology 32 (6): 735–9. December 1991. doi:10.1111/j.1365-2125.1991.tb03982.x. PMID 1768567. 
  26. ↑ PubChem. "Hexobarbital" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/3608. 
  27. ↑ "[Toxicity, narcotic effect, blood level after awakening, elimination from the blood and biotransformation of hexobarbital in rats of different ages after induction with barbital and carbon tetrachloride poisoning]". Archives Internationales de Pharmacodynamie et de Therapie 184 (1): 5–18. March 1970. PMID 5448769. 
  28. ↑ "Naunyn-Schmiedeberg's Archives of Pharmacology | Volumes and issues" (in en). https://link.springer.com/journal/210/volumes-and-issues. 
  29. ↑ "Pharmacologic characteristics of 1-(ortho-toluoxy)2, 3-bis-(2, 2, 2-trichloro-1-hydroxyethoxy)-propane". The Journal of Pharmacology and Experimental Therapeutics 106 (4): 444–52. December 1952. PMID 13023555. https://jpet.aspetjournals.org/content/106/4/444. 
  30. ↑ "Toxicity and depressant action of ethanol and hexobarbital after pretreatment with asparagine". Toxicology and Applied Pharmacology 5 (6): 790–3. November 1963. doi:10.1016/0041-008X(63)90071-1. PMID 14082484. 
  31. ↑ "[On the pharmacology of 5-ethyl-5(3-hydroxyisoamyl)-barbituric acid--a breakdown product of 5-ethyl-5-isoamyl-barbituric acid]". Arzneimittel-Forschung 15 (6): 688–91. June 1965. PMID 5899249. 
  32. ↑ "The Potentiating Effect of 4,5-Dihydro-6-Methyl-2[2-(4-Pyridyl)-Ethyl-3-Pyridazinone (u-320) on Hexobarbital Hypnosis"] (in en). Journal of Pharmacology and Experimental Therapeutics 134 (1): 95–99. 1961-10-01. ISSN 0022-3565. https://jpet.aspetjournals.org/content/134/1/95. 
  33. ↑ 33.0 33.1 33.2 "A Comparative Study of Several Ultrashortacting Barbiturates, Nembutal, and Tribromethanol" (in en). Journal of Pharmacology and Experimental Therapeutics 60 (2): 189–197. 1937-06-01. ISSN 0022-3565. https://jpet.aspetjournals.org/content/60/2/189. 
  34. ↑ "The present status of the barbiturate problem.". Physiological Reviews 19 (4): 472–502. October 1939. doi:10.1152/physrev.1939.19.4.472. 
  35. ↑ Cards on the Table. New York: William Morrow. 1937. pp. 242. ISBN 978-0-06-207373-0. 



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