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2D Structure
Also known as: 40054-69-1, Depas, 4-(2-chlorophenyl)-2-ethyl-9-methyl-6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, Sedekopan, Y-7131, A76xi0hl37
Molecular Formula
C17H15ClN4S
Molecular Weight
342.8  g/mol
InChI Key
VMZUTJCNQWMAGF-UHFFFAOYSA-N
FDA UNII
A76XI0HL37

Etizolam is a thienodiazepine which is chemically related to benzodiazepine (BDZ) drug class; it differs from BDZs in having a benzene ring replaced with a thiophene ring. It is an agonist at GABA-A receptors and possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Initially introduced in 1983 in Japan as treatment for neurological conditions such as anxiety and sleep disorders, etizolam is marketed in Japan, Italy and India. It is not approved for use by FDA in the US; however it remains unscheduled in several states and is legal for research purposes.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene
2.1.2 InChI
InChI=1S/C17H15ClN4S/c1-3-11-8-13-16(12-6-4-5-7-14(12)18)19-9-15-21-20-10(2)22(15)17(13)23-11/h4-8H,3,9H2,1-2H3
2.1.3 InChI Key
VMZUTJCNQWMAGF-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CCC1=CC2=C(S1)N3C(=NN=C3CN=C2C4=CC=CC=C4Cl)C
2.2 Other Identifiers
2.2.1 UNII
A76XI0HL37
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Etizolam, 14c-labeled

2. Y 7131

3. Y-7131

2.3.2 Depositor-Supplied Synonyms

1. 40054-69-1

2. Depas

3. 4-(2-chlorophenyl)-2-ethyl-9-methyl-6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

4. Sedekopan

5. Y-7131

6. A76xi0hl37

7. 4-(o-chlorophenyl)-2-ethyl-9-methyl-6h-thieno(3,2-f)-s-triazolo(4,3-a)(1,4)diazepine

8. Ahr3219;y7131

9. Ncgc00182031-01

10. Etizolamum

11. Etizolam [inn:jan]

12. Etizolamum [inn-latin]

13. Ahr 3219

14. 7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaene

15. Brn 0572740

16. Unii-a76xi0hl37

17. Sedekopan (tn)

18. Etizolam [inn]

19. Etizolam [jan]

20. Etizolam [mi]

21. Etizolam (jp17/inn)

22. Dsstox_cid_3030

23. Etizolam [mart.]

24. Etizolam [who-dd]

25. 6-(o-chlorophenyl)-8-ethyl-1-methyl-4h-s-triazolo(3,4-c)thieno(2,3-e)(1,4)-diazepine

26. 6-(o-chlorphenyl)-8-aethyl-1-methyl-4h-s-triazolo(3,4-c)thieno(2,3-e)(1,4)diazepin [german]

27. 6h-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine, 4-(2-chlorophenyl)-2-ethyl-9-methyl-

28. 8-ethyl-6-(o-chlorophenyl)-1-methyl-4h-s-triazolo(3,4c)thieno(2,3e)-1,4-diazepine

29. Dsstox_rid_76838

30. Dsstox_gsid_23030

31. Schembl42920

32. Zinc1402

33. Chembl1289779

34. Dtxsid0023030

35. Chebi:31583

36. Ahr3219

37. Etizolam 0.1 Mg/ml In Methanol

38. Etizolam 1.0 Mg/ml In Methanol

39. 4c66

40. Hms3652n06

41. Bcp22893

42. Hy-b0677

43. Tox21_112931

44. S4276

45. Akos022185397

46. Db09166

47. Ds-3112

48. 4h-s-triazolo(3,4-c)thieno(2,3-e)(1,4)-diazepine, 6-(o-chlorophenyl)-8-ethyl-1-methyl-

49. 6-(o-chlorphenyl)-8-aethyl-1-methyl-4h-s-triazolo(3,4-c)thieno(2,3-e)(1,4)diazepin

50. Ncgc00182031-05

51. Cas-40054-69-1

52. Sw219903-1

53. A14257

54. D01514

55. Q409966

56. Sr-01000883960

57. Sr-01000883960-1

58. Etizolam Solution, 1.0 Mg/ml In Methanol, Ampule Of 1 Ml, Certified Reference Material

59. 4-(2-chlorophenyl)-2-ethyl-9-methyl-6h-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine

60. 4-(2-chlorophenyl)-2-ethyl-9-methyl-6h-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine

61. 7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene

62. 7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene

63. H4c

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 342.8 g/mol
Molecular Formula C17H15ClN4S
XLogP32.6
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count4
Rotatable Bond Count2
Exact Mass342.0705954 g/mol
Monoisotopic Mass342.0705954 g/mol
Topological Polar Surface Area71.3 Ų
Heavy Atom Count23
Formal Charge0
Complexity474
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

Indicated for the treatment of generalized anxiety disorder with depression, panic disorder and insomnia.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Etizolam is a CNS depressant with anxiolytic, anticonvulsant, sedative-hypnotic and muscle relaxant effects. It acts on the benzodiazepine site of the GABA-A receptor as an agonist to increase inhibitory GABAergic transmission throughout the central nervous system. Studies indicate that etizolam mediates its pharmacological actions with 6 to 10 times more potency than that of diazepam. Clinical human studies performed in Italy showed clinical effectiveness of etizolam in relieving symptoms in patients with generalized anxiety disorders with depressive symptoms. Etizolam also mediates imipramine-like neuropharmacological and behavioral effects, as well as minor effects on cognitive functioning. It is shown to substitute the actions of a short-acting barbiturate, pentobarbitol, in a drug discrimination study. Etizolam is an antagonist at platelet-activating-factor (PAF) receptor and attenuates the recurrence of chronic subdural hematoma after neurosurgery in clinical studies. It is shown to inhibit PAF-induced bronchoconstriction and hypotension.


5.2 MeSH Pharmacological Classification

Tranquilizing Agents

A traditional grouping of drugs said to have a soothing or calming effect on mood, thought, or behavior. Included here are the ANTI-ANXIETY AGENTS (minor tranquilizers), ANTIMANIC AGENTS, and the ANTIPSYCHOTIC AGENTS (major tranquilizers). These drugs act by different mechanisms and are used for different therapeutic purposes. (See all compounds classified as Tranquilizing Agents.)


5.3 ATC Code

N - Nervous system

N05 - Psycholeptics

N05B - Anxiolytics

N05BA - Benzodiazepine derivatives

N05BA19 - Etizolam


5.4 Absorption, Distribution and Excretion

Absorption

Etizolam is well absorbed from the intestines with a biological bioavailability of 93% following oral administration. After a single oral dosing of 0.5mg etizolam, it takes approximately 0.9 hours to reach the peak plasma concentration of 8.3 ng/mL.


Route of Elimination

In a rat study, the amounts of etizolam excreted was 30% in urine was 70% in feces, while the values in a mouse study were 40% in urine and 60% in feces.


Volume of Distribution

Apparent distribution volume was 0.9 0.2 L/kg following a single oral doing of 0.5mg etizolam.


5.5 Metabolism/Metabolites

Biotransformation of etizolam is extensive and involves hydroxylation and conjugation. The main metabolite formed via 1'-hydroxylation is -hydroxyetizolam which retains pharmacological activity comparable to that of the parent drug, indicating that the action of metabolites may contribute to the clinical effects of etizolam. CYP3A4 is predicted to be the main CYP enzyme responsible for mediating etizolam metabolism. CYP2C18 and CYP2C19 are also involved in the metabolic pathways.


Etizolam has known human metabolites that include 7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-ol and alpha-Hydroxyetizolam.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560


5.6 Biological Half-Life

The average elimination half life of etizolam following a single oral dose of 0.5mg is 3.4 hours but may be increased up to 17 hours depending on the rate of metabolism. The main metabolite -hydroxyetizolam displays a longer elimination half life of 8.2 hours.


5.7 Mechanism of Action

Etizolam is selectively a full agonist at GABA-A receptors to increase GABAergic transmission and enhance GABA-induced Cl- currents. It is reported to bind to the benzodiazepine binding site which is located across the interface between the alpha and gamma subunits. Benzodiazapines are reported to only bind to receptors that contain gamma 2 and alpha 1/2/3/5 subunits. Alpha-1-containing receptors mediate the sedative effects of etizolam whereas alpha-2 and alpha-3 subunit-containing receptors mediate the anxiolytic effect. Etizolam shows high potency and affinity towards GABA-A receptor with alpha 1 beta 2 gamma 2S subunit combination. By binding to the regulatory site of the receptor, etizolam potentiates GABA transmission by facilitating the opening of GABA-induced chloride channels. Etizolam is a specific antagonist at PAFR. It inhibits PAF-induced platelet aggregation by inhibiting PAF binding to the receptors located on the surface of platelets with an IC50 of 22nM.