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targets (5) enzymes (5)
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Identification
Name Zopiclone
Accession Number DB01198 (APRD00356)
Type small molecule
Groups approved
Description

Zopiclone is a novel hypnotic agent used in the treatment of insomnia. Its mechanism of action is based on modulating benzodiazepine receptors. In addition to zopiclone’s benzodiazepine pharmacological properties it also has some barbiturate like properties.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • (+-)-zopiclone
  • Zopiclona [INN-Spanish]
  • Zopiclone [Ban:Inn:Jan]
  • Zopiclonum [INN-Latin]
Brand names
  • Amoban
  • Amovane
  • Imovance
  • Imovane
  • Novo-zopiclone
  • Nu-Zopiclone
  • Ran-zopiclone
  • Rhovane
  • Sopivan
  • Ximovan
  • Zimovane
Brand name mixtures Not Available
Categories
  • Hypnotics and Sedatives
CAS number 43200-80-2
Weight Average: 388.808
Monoisotopic: 388.105066147
Chemical Formula C17H17ClN6O3
InChI Key InChIKey=GBBSUAFBMRNDJC-UHFFFAOYSA-N
InChI
InChI=1S/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3
Plain Text
IUPAC Name
6-(5-chloropyridin-2-yl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate
SMILES
CN1CCN(CC1)C(=O)OC1N(C(=O)C2=NC=CN=C12)C1=NC=C(Cl)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Lactams
  • Cyclopyrrolones
Substructures
  • Carbamates and Derivatives
  • Amino Ketones
  • Pyridines and Derivatives
  • Piperazines
  • Ethers
  • Aliphatic and Aryl Amines
  • Aryl Halides
  • Aminopyridines and Derivatives
  • Pyrazines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Lactams
  • Imines
  • Cyclopyrrolones
  • Pyrrolines
Pharmacology
Indication For the short-term treatment of insomnia.
Pharmacodynamics Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABABZ) receptor complex. Subunit modulation of the GABABZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor.
Mechanism of action Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABABZ receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone.
Absorption Rapidly absorbed following oral administration.
Volume of distribution Not Available
Protein binding Approximately 45%
Metabolism

Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 CO2 oxidative decarboxylation
Cytochrome P450 3A4 zopiclone-N-oxide N-oxidation 84 0.054
Cytochrome P450 3A4 N-desmethylzopiclone N-demethylation 78 0.045
Cytochrome P450 2C9 Zopiclone N-oxide N-oxidation
Cytochrome P450 2C9 N-Desmethyl zopiclone N-demethylation
Cytochrome P450 2C8 zopiclone-N-oxide N-oxidation 59 17.9
Cytochrome P450 2C8 N-desmethylzopiclone N-demethylation 71 44.76
Route of elimination Not Available
Half life Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency.
Clearance Not Available
Toxicity Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Tablet Oral 5 mg
Tablet Oral 7.5 mg
Prices
Unit description Cost Unit
Imovane 7.5 mg Tablet 1.41 USD tablet
Imovane 5 mg Tablet 1.11 USD tablet
Apo-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Co Zopiclone 7.5 mg Tablet 0.49 USD tablet
Mylan-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Novo-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Nu-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Pms-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Ran-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Ratio-Zopiclone 7.5 mg Tablet 0.49 USD tablet
Rhovane 7.5 mg Tablet 0.49 USD tablet
Sandoz Zopiclone 7.5 mg Tablet 0.49 USD tablet
Zopiclone 7.5 mg Tablet 0.49 USD tablet
Apo-Zopiclone 5 mg Tablet 0.23 USD tablet
Co Zopiclone 5 mg Tablet 0.23 USD tablet
Mylan-Zopiclone 5 mg Tablet 0.23 USD tablet
Novo-Zopiclone 5 mg Tablet 0.23 USD tablet
Pms-Zopiclone 5 mg Tablet 0.23 USD tablet
Ran-Zopiclone 5 mg Tablet 0.23 USD tablet
Ratio-Zopiclone 5 mg Tablet 0.23 USD tablet
Sandoz Zopiclone 5 mg Tablet 0.23 USD tablet
Zopiclone 5 mg Tablet 0.23 USD tablet
Patents Not Available
Properties
State solid
Melting point 178 oC
Experimental Properties
Property Value Source
water solubility 0.151 mg/mL at 25 oC [MEYLAN,WM et al. (1996)] PhysProp
logP 0.8 PhysProp
Predicted Properties
Property Value Source
water solubility 8.85e-01 g/l ALOGPS
logP 0.97 ALOGPS
logP 0.81 ChemAxon Molconvert
logS -2.64 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 91.76 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 95.89 ChemAxon Molconvert
polarizability 37.67 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Liu HJ, Sato K, Shih HC, Shibuya T, Kawamoto H, Kitagawa H: Pharmacologic studies of the central action of zopiclone: effects on locomotor activity and brain monoamines in rats. Int J Clin Pharmacol Ther Toxicol. 1985 Mar;23(3):121-8. Pubmed
  2. Sato K, Hong YL, Yang MS, Shibuya T, Kawamoto H, Kitagawa H: Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition. Int J Clin Pharmacol Ther Toxicol. 1985 Apr;23(4):204-10. Pubmed
  3. Dundar Y, Dodd S, Strobl J, Boland A, Dickson R, Walley T: Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol. 2004 Jul;19(5):305-22. Pubmed
  4. Blanchard JC, Julou L: Suriclone: a new cyclopyrrolone derivative recognizing receptors labeled by benzodiazepines in rat hippocampus and cerebellum. J Neurochem. 1983 Mar;40(3):601-7. Pubmed
  5. Julou L, Bardone MC, Blanchard JC, Garret C, Stutzmann JM: Pharmacological studies on zopiclone. Pharmacology. 1983;27 Suppl 2:46-58. Pubmed
External Links
Resource Link
KEGG Drug D01372 Link_out
PubChem Compound 5735 Link_out
PubChem Substance 46505233 Link_out
ChemSpider 5533 Link_out
BindingDB 50054136 Link_out
ChEBI 32315 Link_out
ChEMBL 32315 Link_out
Therapeutic Targets Database DAP000427 Link_out
PharmGKB PA10236 Link_out
Drug Product Database 2257580 Link_out
Drugs.com http://www.drugs.com/cdi/eszopiclone.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Zopiclone Link_out
ATC Codes
  • N05CF01
AHFS Codes
  • 28:24.92
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Gamma-aminobutyric-acid receptor subunit alpha-1

Pharmacological action: yes
Actions: potentiator

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P14867 Link_out
Gene: GABRA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol. 2009 Nov 26. Pubmed
  2. Hanson SM, Morlock EV, Satyshur KA, Czajkowski C: Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. 2008 Nov 27;51(22):7243-52. Pubmed
  3. Sanger DJ: The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;18 Suppl 1:9-15; discussion 41, 43-5. Pubmed
  4. Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. Pubmed
  5. Ramerstorfer J, Furtmuller R, Vogel E, Huck S, Sieghart W: The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes. Eur J Pharmacol. 2010 Jun 25;636(1-3):18-27. Epub 2010 Mar 19. Pubmed

2. Gamma-aminobutyric-acid receptor subunit alpha-2

Pharmacological action: yes
Actions: potentiator

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P47869 Link_out
Gene: GABRA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol. 2009 Nov 26. Pubmed
  2. Hanson SM, Morlock EV, Satyshur KA, Czajkowski C: Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. 2008 Nov 27;51(22):7243-52. Pubmed
  3. Ramerstorfer J, Furtmuller R, Vogel E, Huck S, Sieghart W: The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes. Eur J Pharmacol. 2010 Jun 25;636(1-3):18-27. Epub 2010 Mar 19. Pubmed

3. Gamma-aminobutyric-acid receptor subunit alpha-3

Pharmacological action: yes
Actions: potentiator

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P34903 Link_out
Gene: GABRA3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol. 2009 Nov 26. Pubmed
  2. Hanson SM, Morlock EV, Satyshur KA, Czajkowski C: Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. 2008 Nov 27;51(22):7243-52. Pubmed
  3. Ramerstorfer J, Furtmuller R, Vogel E, Huck S, Sieghart W: The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes. Eur J Pharmacol. 2010 Jun 25;636(1-3):18-27. Epub 2010 Mar 19. Pubmed

4. Gamma-aminobutyric-acid receptor subunit alpha-5

Pharmacological action: yes
Actions: potentiator

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P31644 Link_out
Gene: GABRA5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol. 2009 Nov 26. Pubmed
  2. Hanson SM, Morlock EV, Satyshur KA, Czajkowski C: Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. 2008 Nov 27;51(22):7243-52. Pubmed
  3. Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. Pubmed
  4. Ramerstorfer J, Furtmuller R, Vogel E, Huck S, Sieghart W: The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes. Eur J Pharmacol. 2010 Jun 25;636(1-3):18-27. Epub 2010 Mar 19. Pubmed

5. Translocator protein

Pharmacological action: unknown
Actions: agonist

Responsible for the manifestation of peripheral-type benzodiazepine recognition sites and is most likely to comprise binding domains for benzodiazepines and isoquinoline carboxamides. May play a role in the transport of porphyrins and heme

Organism class: human
UniProt ID: P30536 Link_out
Gene: TSPO Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD: Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004 Apr;32(4):447-54. Pubmed

2. Cytochrome P450 2C8

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD: Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004 Apr;32(4):447-54. Pubmed

3. Cytochrome P450 2C9

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Prostaglandin G/H synthase 1

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

5. Cytochrome P450 2E1

Actions: substrate

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 27, 2011 12:31

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.