Enoxolone

Enoxolone
Systematic (IUPAC) name
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid
Clinical data
Trade names Arthrodont, PruClair
AHFS/Drugs.com International Drug Names
Oral, topical
Identifiers
471-53-4
D03AX10
PubChem CID 10114
ChemSpider 9710
ChEBI CHEBI:30853
ChEMBL CHEMBL230006
Chemical data
Formula C30H46O4
470.6838

Enoxolone (INN, BAN), glycyrrhetinic acid or glycyrrhetic acid is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice. It is used in flavoring and it masks the bitter taste of drugs like aloe and quinine. It is effective in the treatment of peptic ulcer and also has expectorant (antitussive) properties.[1] It has some additional pharmacological properties including antiviral, antifungal, antiprotozoal, and antibacterial activities.[2][3][4][5]

Mechanism of action

Glycyrrhetinic acid inhibits the enzymes (15-hydroxyprostaglandin dehydrogenase and delta-13-prostaglandin) that metabolize the prostaglandins PGE-2 and PGF-2α to their respective 15-keto-13,14-dihydro metabolites which are inactive. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach. The effect on gastric acid secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer.

PGF-2α stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy.

The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action.

3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active' cortisol to 'inactive' cortisone in the kidneys. This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase. As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone and increases sodium reabsorption) that work on ENaC channels in the collecting duct. Hypertension develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin and low aldosterone blood level. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure and inhibition of the renin-angiotensin-aldosterone system. Therefore licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase.

Derivatives

Glycyrrhetinic acid derivatives, where R is a variable functional group

In glycyrrhetinic acid, the functional group (R) is a hydroxyl group. Research in 2005 demonstrated that with a proper functional group a very effective glycyrrhetinic artificial sweetener can be obtained.[6] When R is an anionic NHCO(CH2)CO2K side chain, the sweetening effect is found to 1200 times that of sugar (human sensory panel data). A shorter or longer spacer reduces the sweetening effect. One explanation is that the taste bud cell receptor has 1.3 nanometers (13 angstroms) available for docking with the sweetener molecule. In addition the sweetener molecule requires three proton donor positions of which two reside at the extremities to be able to interact efficiently with the receptor cavity.

A synthetic analog, carbenoxolone, was developed in Britain. Both glycyrrhetinic acid and carbenoxolone have a modulatory effect on neural signaling through gap junction channels.

Acetoxolone, the acetyl derivative of glycyrrhetinic acid, is a drug used in the treatment of peptic ulcer and gastroesophageal reflux disease.

References

  1. ↑ Chandler, RF (1985). "Liquorice, more than just a flavour". Canadian Pharmaceutical Journal (118): 420–4.
  2. ↑ Badam, L., Amagaya, S. and Pollard, B. (1997). "In vitro activity of licorice and glycyrrhetinic acid on Japanese encephalitis virus.". J. Community Dis. 29: 91–99.
  3. ↑ Fuji, H.Y., Tian, J. and Luka, C. (1986). "Effect of glycyrrhetinic acid on influenza virus and pathogenic bacteria.". Bull. Chin. Mater. Med. 11: 238–241.
  4. ↑ Guo, N., Takechi, M. and Uno, C. (1991). "Protective effect of glycyrrhizine in mice with systemic Candida albicans infection and its mechanism". J. Pharm. Pharmacol. 12 (5): 380–383. PMID 1839259.
  5. ↑ Salari, M. H., Sohrabi, N., Kadkhoda, Z., and Khalili, M. B. (2003). "Antibacterial effects of Enoxolone on periodontopathogenic and capnophilic bacteria isolated from specimens of periodontitis patients". Iran. Biomed. J. 7: 39–42.
  6. ↑ Ijichi, So; Seizo Tamagaki (2005). "Molecular Design of Sweet Tasting Compounds Based on 3β-Amino-3β-deoxy-18β-glycyrrhetinic Acid: Amido Functionality Eliciting Tremendous Sweetness". Chemistry Letters 34 (3): 356. doi:10.1246/cl.2005.356. Retrieved 2010-09-28.

Further reading