Etizolam
Identification
- Summary
Etizolam is a thienodiazepine derivative used to treat anxiety and insomnia.
- Generic Name
- Etizolam
- DrugBank Accession Number
- DB09166
- Background
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.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
- Weight
- Average: 342.846
Monoisotopic: 342.070594897 - Chemical Formula
- C17H15ClN4S
- Synonyms
- 4-(o-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno(3,2-f)-s-triazolo(4,3-a)(1,4)diazepine
- Etizolam
Pharmacology
- Indication
Indicated for the treatment of generalized anxiety disorder with depression, panic disorder and insomnia.
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- Contraindications & Blackbox Warnings
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- Pharmacodynamics
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 2,3,4. 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 8. Etizolam is an antagonist at platelet-activating-factor (PAF) receptor and attenuates the recurrence of chronic subdural hematoma after neurosurgery in clinical studies 9. It is shown to inhibit PAF-induced bronchoconstriction and hypotension 5.
- Mechanism of action
Etizolam is selectively a full agonist at GABA-A receptors to increase GABAergic transmission and enhance GABA-induced Cl- currents 1. 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 7. Alpha-1-containing receptors mediate the sedative effects of etizolam whereas alpha-2 and alpha-3 subunit-containing receptors mediate the anxiolytic effect 7. Etizolam shows high potency and affinity towards GABA-A receptor with alpha 1 beta 2 gamma 2S subunit combination 1. By binding to the regulatory site of the receptor, etizolam potentiates GABA transmission by facilitating the opening of GABA-induced chloride channels 7. 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 5.
Target Actions Organism AGABA(A) Receptor positive allosteric modulatorHumans AGABA(A) Receptor Benzodiazepine Binding Site ligandHumans UPlatelet-activating factor receptor antagonistHumans - 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 9.
- Volume of distribution
Apparent distribution volume was 0.9 ± 0.2 L/kg following a single oral doing of 0.5mg etizolam 9.
- Protein binding
Not Available
- Metabolism
Biotransformation of etizolam is extensive and involves hydroxylation and conjugation 9. The main metabolite formed via 1'-hydroxylation is α-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 6. CYP3A4 is predicted to be the main CYP enzyme responsible for mediating etizolam metabolism. CYP2C18 and CYP2C19 are also involved in the metabolic pathways 9,5.
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- 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 9.
- 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 9. The main metabolite α-hydroxyetizolam displays a longer elimination half life of 8.2 hours 6.
- Clearance
Not Available
- Adverse Effects
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- Toxicity
Major adverse effects include drowsiness, sedation, muscle weakness and incoordination, fainting, headache, confusion, depression, slurred speech, visual disturbances and changes in libido and tremor 8. Flumazenil is a competitive antagonist of GABA-A receptors and can be also used to reverse the effect of etizolam overdosage. Etizolam demonstrates no effects on fertility, development and teratogenicity 9. LD50 values of etizolam when delivered orally, intraperitoneally, and subcutaneously are 3509mg/kg, 825mg/kg, and >5000mg/kg in rats, respectively, and 3070mg/kg, 783mg/kg and 5000mg/kg in mice, respectively MSDS.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Etizolam is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Etizolam can be increased when it is combined with Abametapir. Abatacept The metabolism of Etizolam can be increased when combined with Abatacept. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Etizolam. Acenocoumarol The metabolism of Etizolam can be decreased when combined with Acenocoumarol. - Food Interactions
- Not Available
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Arophalm (Nichi-Iko Pharmaceutical) / Capsafe (Ohara Yakuhin) / Dezolam (Taisho Yakuhin) / E1 (Aarpik) / Eticalm (Towa Yakuhin) / Etisedan (Kyowa Yakuhin) / Etizolan (Kobayashi Kako) / Mozun (Tatsumi Kagaku) / New Zomnia (Molekule) / Nonnerv (Nisshin Pharmaceutical) / Palgin (Fujinaga Seiyaku) / Sylkam (Dr. Reddy's)
Categories
- ATC Codes
- N05BA19 — Etizolam
- Drug Categories
- Anti-Anxiety Agents
- Benzazepines
- Benzodiazepine hypnotics and sedatives
- Benzodiazepines and benzodiazepine derivatives
- Benzodiazepinones
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP2C18 Substrates
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Hypnotics and Sedatives
- Muscle Relaxants
- Muscle Relaxants, Centrally Acting Agents
- Nervous System
- Psycholeptics
- Psychotropic Drugs
- Tranquilizing Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as thienodiazepines. These are heteropolycyclic containing a thiophene ring fused to a diazepine ring. Thiophene is 5-membered ring consisting of four carbon and one sulfur atoms. Diazepine is a 7-membered ring consisting of five carbon and two nitrogen atoms.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Thienodiazepines
- Sub Class
- Not Available
- Direct Parent
- Thienodiazepines
- Alternative Parents
- 2,3,5-trisubstituted thiophenes / Chlorobenzenes / 1,4-diazepines / Aryl chlorides / Triazoles / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds show 2 more
- Substituents
- 1,2,4-triazole / 2,3,5-trisubstituted thiophene / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Chlorobenzene / Halobenzene show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- A76XI0HL37
- CAS number
- 40054-69-1
- InChI Key
- VMZUTJCNQWMAGF-UHFFFAOYSA-N
- 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
- IUPAC Name
- 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
- SMILES
- CCC1=CC2=C(S1)N1C(C)=NN=C1CN=C2C1=CC=CC=C1Cl
References
- Synthesis Reference
Tahara T, Araki K, Shiroki M, Matsuo H, Munakata T. Syntheses and structure-activity relationships of 6-aryl-4H-s-triazolo[3,4-c]thieno[2,3-e] [1,4]diazepines. Arzneimittelforschung. 1978;28(7):1153-8.
- General References
- Sanna E, Pau D, Tuveri F, Massa F, Maciocco E, Acquas C, Floris C, Fontana SN, Maira G, Biggio G: Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions. Arzneimittelforschung. 1999 Feb;49(2):88-95. [Article]
- Casacchia M, Bolino F, Ecari U: Etizolam in the treatment of generalized anxiety disorder: a double-blind study versus placebo. Curr Med Res Opin. 1990;12(4):215-23. [Article]
- Bertolino A, Mastucci E, Porro V, Corfiati L, Palermo M, Ecari U, Ceccarelli G: Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial. J Int Med Res. 1989 Sep-Oct;17(5):455-60. [Article]
- Pariante F, Caddeo S, Ecari U: Etizolam in the treatment of generalized anxiety disorder associated with depressive symptoms. Curr Med Res Opin. 1989;11(9):543-9. [Article]
- Mikashima H, Takehara S, Muramoto Y, Khomaru T, Terasawa M, Tahara T, Maruyama Y: An antagonistic activity of etizolam on platelet-activating factor (PAF). In vitro effects on platelet aggregation and PAF receptor binding. Jpn J Pharmacol. 1987 Aug;44(4):387-91. [Article]
- Fracasso C, Confalonieri S, Garattini S, Caccia S: Single and multiple dose pharmacokinetics of etizolam in healthy subjects. Eur J Clin Pharmacol. 1991;40(2):181-5. [Article]
- 43. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 533-538). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
- US Drug Enforcement Administration: ETIZOLAM Drug information [Link]
- World Health Organization: Etizolam (INN) Pre-Review Report [Link]
- External Links
- Human Metabolome Database
- HMDB0041890
- KEGG Drug
- D01514
- PubChem Compound
- 3307
- PubChem Substance
- 310265075
- ChemSpider
- 3191
- ChEBI
- 31583
- ChEMBL
- CHEMBL1289779
- ZINC
- ZINC000000001402
- Wikipedia
- Etizolam
- MSDS
- Download (31.4 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution / drops Oral 0.05 % Tablet 0.5 MG Tablet 1 MG Tablet, film coated 0.5 MG Tablet, film coated 1 MG Capsule Solution / drops Oral Tablet Tablet, coated - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 147-148 World Health Organization: Etizolam (INN) Pre-Review Report water solubility Practically insoluble World Health Organization: Etizolam (INN) Pre-Review Report - Predicted Properties
Property Value Source Water Solubility 0.0425 mg/mL ALOGPS logP 2.98 ALOGPS logP 4.06 Chemaxon logS -3.9 ALOGPS pKa (Strongest Acidic) 18.16 Chemaxon pKa (Strongest Basic) 4.55 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 43.07 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 104.72 m3·mol-1 Chemaxon Polarizability 35.64 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-06tf-8189000000-7a2ceb12ff7824adfa15 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-0009000000-c9b4331e3553da1208bc Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-4009000000-639c0ec8bccec8e12d7d Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000x-2029000000-30006b296c393436e101 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-0009000000-49b0610aae807fa4f9c9 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-03fr-0019000000-a135f67e65ec5bbb33c8 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001r-8292000000-2a617f693bdc973855fc Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 181.3386255 predictedDarkChem Lite v0.1.0 [M-H]- 166.67342 predictedDeepCCS 1.0 (2019) [M+H]+ 181.8805255 predictedDarkChem Lite v0.1.0 [M+H]+ 169.03142 predictedDeepCCS 1.0 (2019) [M+Na]+ 182.3979255 predictedDarkChem Lite v0.1.0 [M+Na]+ 175.75893 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Positive allosteric modulator
- Curator comments
- The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Components:
References
- Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
- Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Ligand
- Curator comments
- Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.
- General Function
- Inhibitory extracellular ligand-gated ion channel activity
- Specific Function
- Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Components:
References
- Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
- Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Platelet activating factor receptor activity
- Specific Function
- Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth-muscle contractile and hypotensive activity. Seems to mediate its action via ...
- Gene Name
- PTAFR
- Uniprot ID
- P25105
- Uniprot Name
- Platelet-activating factor receptor
- Molecular Weight
- 39203.075 Da
References
- Mikashima H, Takehara S, Muramoto Y, Khomaru T, Terasawa M, Tahara T, Maruyama Y: An antagonistic activity of etizolam on platelet-activating factor (PAF). In vitro effects on platelet aggregation and PAF receptor binding. Jpn J Pharmacol. 1987 Aug;44(4):387-91. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, Tateishi T, Otani K: Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism. Eur J Clin Pharmacol. 2004 Aug;60(6):427-30. Epub 2004 Jul 1. [Article]
- World Health Organization: Etizolam (INN) Pre-Review Report [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C18
- Uniprot ID
- P33260
- Uniprot Name
- Cytochrome P450 2C18
- Molecular Weight
- 55710.075 Da
References
- World Health Organization: Etizolam (INN) Pre-Review Report [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Fukasawa T, Yasui-Furukori N, Suzuki A, Inoue Y, Tateishi T, Otani K: Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol. 2005 Dec;61(11):791-5. Epub 2005 Nov 1. [Article]
- Yamamoto T, Furihata K, Hisaka A, Moritoyo T, Ogoe K, Kusayama S, Motohashi K, Mori A, Iwatsubo T, Suzuki H: Notable Drug-Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19. J Clin Pharmacol. 2017 Nov;57(11):1491-1499. doi: 10.1002/jcph.956. Epub 2017 Jul 5. [Article]
- WHO Critical Review: Etizolam [File]
Drug created at October 13, 2015 23:46 / Updated at May 07, 2021 21:06