Quazepam

Identification

Summary

Quazepam is a long-acting benzodiazepine used to manage insomnia.

Brand Names
Doral
Generic Name
Quazepam
DrugBank Accession Number
DB01589
Background

Quazepam is a trifluoroethyl benzodiazepine derivative. It was first approved in the US in 1985 and is used as a hypnotic for the treatment of insomnia.6

It appears to be unique amongst other benzodiazepine derivatives in its relatively high affinity for sleep-promoting α1 subunit-containing GABAA receptors and low affinity for other receptors.5

Type
Small Molecule
Groups
Approved, Illicit
Structure
Weight
Average: 386.794
Monoisotopic: 386.026759579
Chemical Formula
C17H11ClF4N2S
Synonyms
  • Quazepam
  • Quazepamum
External IDs
  • SCH 16134
  • SCH-16134

Pharmacology

Indication

Quazepam is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofInsomnia••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Benzodiazepines, including quazepam, exert their sedative and anxiolytic effects by potentiating the effects of endogenous GABA, the primary inhibitory neurotransmitter in the central nervous system.3

Mechanism of action

Like other benzodiazepines, quazepam likely exerts its effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain.4 GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy.

Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased.4

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Absorption

The half-life of absorption following oral administration is approximately 30 minutes.6 Peak plasma concentration (Cmax) is approximately 20 ng/mL and occurs around 2 hours following administration.6

Volume of distribution

Not Available

Protein binding

Quazepam and both of its major metabolites are >95% protein-bound in plasma.6

Metabolism

Quazepam undergoes extensive hepatic metabolism, primarily via CYP3A4 and to a lesser extent via CYP2C9, CYP2C19, and FMO1.1 Quazepam is first metabolized to 2-oxoquazepam, which is then further metabolized to both N-desalkyl-2-oxoquazepam (norflurazepam) and 3-hydroxy-2-oxoquazepam.1,2 Both 2-oxoquazepam and N-desalkyl-2-oxoquazepam exert CNS depressant activity.6

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Route of elimination

Over the course of five days following the administration of radiolabeled quazepam, approximately 31% of the administered dose appeared in the urine and 23% appeared in the feces.6 Unchanged drug appeared in only trace amounts in the urine.6

Half-life

The mean elimination half-lives of both quazepam and 2-oxoquazepam is approximately 39 hours.6 The mean elimination half-life of N-desalkyl-2-oxoquazepam is approximately 73 hours.6

Clearance

Not Available

Adverse Effects
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Toxicity

Benzodiazepine overdose is typically characterized by central nervous system depression ranging from mild drowsiness to coma.6 Mild-to-moderate cases may involve relatively minor symptoms like drowsiness, dysarthria, confusion, and ataxia, while severe cases may lead to respiratory depression and coma. In rare cases, paradoxical disinhibitory reactions (e.g. agitation, violent behaviour, impulsivity) may occur.

The management of benzodiazepine overdose should involve general supportive measures as clinically indicated. Flumazenil is a benzodiazepine receptor antagonist which is indicated for the complete or partial reversal of benzodiazepine-induced sedation, although its appropriateness is highly dependent on the clinical status and history of the patient.6 The use of flumazenil can lead to withdrawal and significant adverse reactions (e.g. seizures), especially in the context of mixed overdoses and in long-term benzodiazepine users with an established physical dependency, and its use is contraindicated in patients using benzodiazepines for potentially life-threatening conditions (e.g. status epilepticus).6 If the decision is made to use flumazenil, it should be used as specified in its prescribing information and as an adjunct alongside general supportive management.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Quazepam is combined with 1,2-Benzodiazepine.
AbametapirThe serum concentration of Quazepam can be increased when it is combined with Abametapir.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Quazepam.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Quazepam.
AgomelatineThe risk or severity of CNS depression can be increased when Quazepam is combined with Agomelatine.
Food Interactions
  • Avoid alcohol. Ingesting alcohol may increase the drowsiness and CNS depression caused by quazepam.

Products

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International/Other Brands
Dormalin
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DoralTablet15 mg/1OralPhysicians Total Care, Inc.1994-03-022002-06-30US flag
DoralTablet15 mg/1OralNuro Pharma, Inc.1985-12-272014-12-18US flag
DoralTablet15 mg/1OralGalt Pharmaceuticals, LLC2017-07-19Not applicableUS flag
DoralTablet15 mg/1OralQuestcor Pharmaceuticals, Inc.1985-12-272013-06-20US flag
QuazepamTablet15 mg/1OralUnit Dose Services2013-08-082015-10-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
QuazepamTablet15 mg/1OralAtland Pharmaceuticals, Llc2018-03-20Not applicableUS flag

Categories

ATC Codes
N05CD10 — Quazepam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,4-benzodiazepines
Alternative Parents
Fluorobenzenes / Aryl fluorides / Aryl chlorides / Thiolactams / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Thiocarbonyl compounds / Organopnictogen compounds / Organofluorides
show 3 more
Substituents
1,4-benzodiazepine / Alkyl fluoride / Alkyl halide / Aromatic heteropolycyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Fluorobenzene
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzodiazepine (CHEBI:8694)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
JF8V0828ZI
CAS number
36735-22-5
InChI Key
IKMPWMZBZSAONZ-UHFFFAOYSA-N
InChI
InChI=1S/C17H11ClF4N2S/c18-10-5-6-14-12(7-10)16(11-3-1-2-4-13(11)19)23-8-15(25)24(14)9-17(20,21)22/h1-7H,8-9H2
IUPAC Name
7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-thione
SMILES
FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=C1C=C(Cl)C=C2

References

General References
  1. Miura M, Ohkubo T: In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions. Xenobiotica. 2004 Nov-Dec;34(11-12):1001-11. [Article]
  2. Zampaglione N, Hilbert JM, Ning J, Chung M, Gural R, Symchowicz S: Disposition and metabolic fate of 14C-quazepam in man. Drug Metab Dispos. 1985 Jan-Feb;13(1):25-9. [Article]
  3. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD: Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013 Summer;13(2):214-23. [Article]
  4. 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]
  5. Moniri NH: Reintroduction of quazepam: an update on comparative hypnotic and adverse effects. Int Clin Psychopharmacol. 2019 Nov;34(6):275-285. doi: 10.1097/YIC.0000000000000277. [Article]
  6. FDA Approved Drug Products: Doral (quazepam) tablets for oral use [Link]
Human Metabolome Database
HMDB0015528
KEGG Drug
D00457
KEGG Compound
C07336
PubChem Compound
4999
PubChem Substance
46505952
ChemSpider
4825
RxNav
35185
ChEBI
8694
ChEMBL
CHEMBL1200472
ZINC
ZINC000000538266
Therapeutic Targets Database
DAP000690
PharmGKB
PA164744373
Drugs.com
Drugs.com Drug Page
Wikipedia
Quazepam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Physicians Total Care Inc.
  • Questcor
Dosage Forms
FormRouteStrength
TabletOral15 mg/1
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7608616No2009-10-272028-06-03US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)137.5-139 °CPhysProp
water solubilityInsolublehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2023/018708s029lbl.pdf
logP4.03SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.00231 mg/mLALOGPS
logP4.76ALOGPS
logP5.06Chemaxon
logS-5.2ALOGPS
pKa (Strongest Acidic)18.93Chemaxon
pKa (Strongest Basic)2.59Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count1Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area15.6 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity93.47 m3·mol-1Chemaxon
Polarizability33.99 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9385
Blood Brain Barrier+0.9789
Caco-2 permeable+0.5748
P-glycoprotein substrateSubstrate0.5341
P-glycoprotein inhibitor IInhibitor0.9324
P-glycoprotein inhibitor IIInhibitor0.8253
Renal organic cation transporterInhibitor0.6883
CYP450 2C9 substrateNon-substrate0.8255
CYP450 2D6 substrateNon-substrate0.8135
CYP450 3A4 substrateSubstrate0.5133
CYP450 1A2 substrateInhibitor0.7023
CYP450 2C9 inhibitorInhibitor0.5757
CYP450 2D6 inhibitorNon-inhibitor0.6337
CYP450 2C19 inhibitorInhibitor0.688
CYP450 3A4 inhibitorInhibitor0.7937
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9484
Ames testNon AMES toxic0.6683
CarcinogenicityNon-carcinogens0.7273
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.9195 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.978
hERG inhibition (predictor II)Inhibitor0.6396
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0gb9-3029000000-7fdbd3548f8dc40c67aa
Mass Spectrum (Electron Ionization)MSsplash10-05aa-3988000000-ca1cf29da979ef46dd6c
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0009000000-f228b7c1ba73e80a4360
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0009000000-0195f9117569eb666473
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0009000000-54eee29879b6b49c9db8
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-2009000000-68a3dc318ec873b7c56a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014s-0349000000-55c28e66286a19e800f1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-008i-4911000000-e3d3a53d031844cc503f
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-176.2374232
predicted
DarkChem Lite v0.1.0
[M-H]-178.92126
predicted
DeepCCS 1.0 (2019)
[M+H]+176.8136232
predicted
DarkChem Lite v0.1.0
[M+H]+181.27925
predicted
DeepCCS 1.0 (2019)
[M+Na]+176.7332232
predicted
DarkChem Lite v0.1.0
[M+Na]+188.37138
predicted
DeepCCS 1.0 (2019)

Targets

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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
  1. 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]
  2. 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
  1. 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]
  2. 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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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
  1. Sugimoto K, Araki N, Ohmori M, Harada K, Cui Y, Tsuruoka S, Kawaguchi A, Fujimura A: Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam. Eur J Clin Pharmacol. 2006 Mar;62(3):209-15. doi: 10.1007/s00228-005-0071-1. Epub 2006 Jan 17. [Article]
  2. Kawaguchi A, Ohmori M, Tsuruoka S, Nishiki K, Harada K, Miyamori I, Yano R, Nakamura T, Masada M, Fujimura A: Drug interaction between St John's Wort and quazepam. Br J Clin Pharmacol. 2004 Oct;58(4):403-10. doi: 10.1111/j.1365-2125.2004.02171.x. [Article]
  3. Miura M, Ohkubo T: In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions. Xenobiotica. 2004 Nov-Dec;34(11-12):1001-11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
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
  1. Miura M, Ohkubo T: In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions. Xenobiotica. 2004 Nov-Dec;34(11-12):1001-11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Sugimoto K, Araki N, Ohmori M, Harada K, Cui Y, Tsuruoka S, Kawaguchi A, Fujimura A: Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam. Eur J Clin Pharmacol. 2006 Mar;62(3):209-15. doi: 10.1007/s00228-005-0071-1. Epub 2006 Jan 17. [Article]

Drug created at August 29, 2007 15:30 / Updated at February 10, 2023 08:55