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Identification
NameFlunitrazepam
Accession NumberDB01544
TypeSmall Molecule
GroupsApproved, Illicit
Description

A benzodiazepine with pharmacologic actions similar to those of diazepam that can cause anterograde amnesia. Some reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. The United States Government has banned the importation of this drug. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
FlunitrazepamumLatinINN
RohypnolNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
HipnosedonRoche
HypnodormAlphapharm
NarcozepRoche
RohypnolRoche
RoipnolRoche
Brand mixturesNot Available
Categories
CAS number1622-62-4
WeightAverage: 313.2832
Monoisotopic: 313.08626947
Chemical FormulaC16H12FN3O3
InChI KeyPPTYJKAXVCCBDU-UHFFFAOYSA-N
InChI
InChI=1S/C16H12FN3O3/c1-19-14-7-6-10(20(22)23)8-12(14)16(18-9-15(19)21)11-4-2-3-5-13(11)17/h2-8H,9H2,1H3
IUPAC Name
5-(2-fluorophenyl)-1-methyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
CN1C2=C(C=C(C=C2)[N+]([O-])=O)C(=NCC1=O)C1=CC=CC=C1F
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzodiazepines
SubclassNot Available
Direct parentBenzodiazepines
Alternative parentsNitrobenzenes; Fluorobenzenes; Aryl Fluorides; Tertiary Carboxylic Acid Amides; Nitronic Acids; Tertiary Amines; Nitro Compounds; Polyamines; Carboxylic Acids; Organic Oxoazanium Compounds; Organofluorides
Substituentsnitrobenzene; fluorobenzene; aryl fluoride; aryl halide; benzene; tertiary carboxylic acid amide; nitronic acid; tertiary amine; carboxamide group; nitro compound; polyamine; carboxylic acid; organic oxoazanium; carboxylic acid derivative; organohalogen; organofluoride; organonitrogen compound; amine
Classification descriptionThis compound belongs to the benzodiazepines. These are organic compounds containing a benzene ring fused to either isomers of diazepine(unsaturated seven-member heterocycle with two nitrogen atoms replacing two carbon atoms).
Pharmacology
IndicationFor short-term treatment of severe insomnias, that are not responsive to other hypnotics.
PharmacodynamicsFlunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries.
Mechanism of actionBenzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
Absorption50% (suppository) and 64-77% (oral)
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half life18-26 hours
ClearanceNot Available
ToxicitySymptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9922
Blood Brain Barrier + 0.973
Caco-2 permeable + 0.5257
P-glycoprotein substrate Substrate 0.6717
P-glycoprotein inhibitor I Non-inhibitor 0.6428
P-glycoprotein inhibitor II Non-inhibitor 0.9094
Renal organic cation transporter Non-inhibitor 0.713
CYP450 2C9 substrate Non-substrate 0.7621
CYP450 2D6 substrate Non-substrate 0.8932
CYP450 3A4 substrate Substrate 0.725
CYP450 1A2 substrate Non-inhibitor 0.5691
CYP450 2C9 substrate Non-inhibitor 0.5163
CYP450 2D6 substrate Non-inhibitor 0.8776
CYP450 2C19 substrate Inhibitor 0.5957
CYP450 3A4 substrate Inhibitor 0.5626
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5555
Ames test AMES toxic 0.9108
Carcinogenicity Non-carcinogens 0.7209
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.8125 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9869
hERG inhibition (predictor II) Non-inhibitor 0.8074
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point166-167 °CKariss, J. and Newmark, H.L.; U.S. Patent 3,116,203; December 31, 1963; assigned to Hoffmann-la Roche Inc.
 Kariss, J. and Newmark, H.L.; US. Patent 3,123,529; March 3,1964; assigned to Hoffmann-La Roche Inc. 
Keiler, O., Steiger, N. and Sternbach, L.H.; U.S. Patent 3,203,990; August 31, 1965; assigned to Hoffmann-La Roche Inc.
logP2.06HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00858ALOGPS
logP2.2ALOGPS
logP2.55ChemAxon
logS-4.6ALOGPS
pKa (Strongest Basic)1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area78.49 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity82.55 m3·mol-1ChemAxon
Polarizability29.6 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Kariss, J. and Newmark, H.L.; U.S. Patent 3,116,203; December 31, 1963; assigned to Hoffmann-la Roche Inc.
 Kariss, J. and Newmark, H.L.; US. Patent 3,123,529; March 3,1964; assigned to Hoffmann-La Roche Inc. 
Keiler, O., Steiger, N. and Sternbach, L.H.; U.S. Patent 3,203,990; August 31, 1965; assigned to Hoffmann-La Roche Inc.

General Reference
  1. Rickels K: The clinical use of hypnotics: indications for use and the need for a variety of hypnotics. Acta Psychiatr Scand Suppl. 1986;332:132-41. Pubmed
  2. Robertson MD, Drummer OH: Postmortem drug metabolism by bacteria. J Forensic Sci. 1995 May;40(3):382-6. Pubmed
  3. Oelschlager H: [Chemical and pharmacologic aspects of benzodiazepines] Schweiz Rundsch Med Prax. 1989 Jul 4;78(27-28):766-72. Pubmed
  4. Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A: Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002 Apr;25(4):441-5. Pubmed
  5. Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. Pubmed
External Links
ResourceLink
KEGG DrugD01230
PubChem Compound3380
PubChem Substance46504553
ChemSpider3263
BindingDB25878
Therapeutic Targets DatabaseDAP000931
PharmGKBPA164781320
WikipediaFlunitrazepam
ATC CodesN05CD03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
ClozapineIncreased risk of toxicity
Food Interactions
  • Avoid alcohol.
  • Avoid excessive quantities of coffee or tea (Caffeine).
  • Avoid taking with grapefruit juice.
  • Take with food.

Targets

1. Translocator protein

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Translocator protein P30536 Details

References:

  1. Katz Y, Weizman R, Weizman A, Gavish M: Disulfiram and diethyldithiocarbamate are competitive inhibitors at the peripheral benzodiazepine receptor. J Pharmacol Exp Ther. 1992 Jul;262(1):394-7. Pubmed
  2. Papadopoulos V, Berkovich A, Krueger KE, Costa E, Guidotti A: Diazepam binding inhibitor and its processing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors. Endocrinology. 1991 Sep;129(3):1481-8. Pubmed
  3. Papadopoulos V, Nowzari FB, Krueger KE: Hormone-stimulated steroidogenesis is coupled to mitochondrial benzodiazepine receptors. Tropic hormone action on steroid biosynthesis is inhibited by flunitrazepam. J Biol Chem. 1991 Feb 25;266(6):3682-7. Pubmed
  4. Awad M, Gavish M: Solubilization of peripheral-type benzodiazepine binding sites from cat cerebral cortex. J Neurochem. 1989 Jun;52(6):1880-5. Pubmed
  5. Gandolfo P, Patte C, Leprince J, Thoumas JL, Vaudry H, Tonon MC: The stimulatory effect of the octadecaneuropeptide (ODN) on cytosolic Ca2+ in rat astrocytes is not mediated through classical benzodiazepine receptors. Eur J Pharmacol. 1997 Mar 19;322(2-3):275-81. Pubmed
  6. Poisnel G, Dhilly M, Le Boisselier R, Barre L, Debruyne D: Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced mu-opioid receptor regulation. J Pharmacol Sci. 2009 May;110(1):36-46. Pubmed

2. Gamma-aminobutyric acid receptor subunit alpha-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-2 P47869 Details

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
  3. Oelschlager H: [Chemical and pharmacologic aspects of benzodiazepines] Schweiz Rundsch Med Prax. 1989 Jul 4;78(27-28):766-72. Pubmed
  4. Oblak AL, Gibbs TT, Blatt GJ: Reduced GABA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 2010 Sep 18. Pubmed
  5. You H, Kozuska JL, Paulsen IM, Dunn SM: Benzodiazepine modulation of the rat GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes. Neuropharmacology. 2010 Nov;59(6):527-33. Epub 2010 Jul 16. Pubmed
  6. Skilbeck KJ, O’Reilly JN, Johnston GA, Hinton T: Antipsychotic drug administration differentially affects [3H]muscimol and [3H]flunitrazepam GABA receptor binding sites. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):492-8. Epub 2007 Oct 10. Pubmed

3. Gamma-aminobutyric acid receptor subunit alpha-4

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-4 P48169 Details

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
  3. Oblak AL, Gibbs TT, Blatt GJ: Reduced GABA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 2010 Sep 18. Pubmed
  4. You H, Kozuska JL, Paulsen IM, Dunn SM: Benzodiazepine modulation of the rat GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes. Neuropharmacology. 2010 Nov;59(6):527-33. Epub 2010 Jul 16. Pubmed
  5. Skilbeck KJ, O’Reilly JN, Johnston GA, Hinton T: Antipsychotic drug administration differentially affects [3H]muscimol and [3H]flunitrazepam GABA receptor binding sites. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):492-8. Epub 2007 Oct 10. Pubmed

4. Gamma-aminobutyric acid receptor subunit alpha-5

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-5 P31644 Details

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
  3. Oblak AL, Gibbs TT, Blatt GJ: Reduced GABA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 2010 Sep 18. Pubmed
  4. You H, Kozuska JL, Paulsen IM, Dunn SM: Benzodiazepine modulation of the rat GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes. Neuropharmacology. 2010 Nov;59(6):527-33. Epub 2010 Jul 16. Pubmed

5. Gamma-aminobutyric acid receptor subunit alpha-6

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-6 Q16445 Details

References:

  1. Santhakumar V, Hanchar HJ, Wallner M, Olsen RW, Otis TS: Contributions of the GABAA receptor alpha6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the alpha6 gene. J Neurosci. 2006 Mar 22;26(12):3357-64. Pubmed
  2. You H, Kozuska JL, Paulsen IM, Dunn SM: Benzodiazepine modulation of the rat GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes. Neuropharmacology. 2010 Nov;59(6):527-33. Epub 2010 Jul 16. Pubmed
  3. Skilbeck KJ, O’Reilly JN, Johnston GA, Hinton T: Antipsychotic drug administration differentially affects [3H]muscimol and [3H]flunitrazepam GABA receptor binding sites. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):492-8. Epub 2007 Oct 10. Pubmed

6. Gamma-aminobutyric acid receptor subunit alpha-3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-3 P34903 Details

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
  3. You H, Kozuska JL, Paulsen IM, Dunn SM: Benzodiazepine modulation of the rat GABAA receptor alpha4beta3gamma2L subtype expressed in Xenopus oocytes. Neuropharmacology. 2010 Nov;59(6):527-33. Epub 2010 Jul 16. Pubmed

Enzymes

1. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

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

2. UDP-glucuronosyltransferase 2B7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

References:

  1. Thomassin J, Tephly TR: Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by [3H]flunitrazepam. Mol Pharmacol. 1990 Sep;38(3):294-8. Pubmed
  2. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

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

4. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

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

5. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

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

6. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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

7. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

8. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Tassaneeyakul W, Birkett DJ, Miners JO: Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica. 1998 Mar;28(3):293-301. Pubmed

9. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. Pubmed

10. UDP-glucuronosyltransferase 1-3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-3 P35503 Details

References:

  1. Cheng Z, Rios GR, King CD, Coffman BL, Green MD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci. 1998 Sep;45(1):52-7. Pubmed

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Drug created on July 31, 2007 07:10 / Updated on April 23, 2014 15:31