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Identification
NameDebrisoquin
Accession NumberDB04840
TypeSmall Molecule
GroupsApproved
Description

An adrenergic neuron-blocking drug similar in effects to guanethidine. It is also noteworthy in being a substrate for a polymorphic cytochrome P-450 enzyme. Persons with certain isoforms of this enzyme are unable to properly metabolize this and many other clinically important drugs. They are commonly referred to as having a debrisoquin 4-hydroxylase polymorphism. [PubChem]

Structure
Thumb
Synonyms
Debrisochinum
Debrisoquin
Debrisoquina
Debrisoquine
Debrisoquinum
Isocaramidine
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
Bonipresslkapharm
DeclinaxRoche
TendorChinoin
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Debrisoquin sulfate
581-88-4
Thumb
  • InChI Key: CAYGYVYWRIHZCQ-UHFFFAOYSA-N
  • Monoisotopic Mass: 448.189274104
  • Average Mass: 448.539
DBSALT000370
Categories
UNIIX31CDK040E
CAS number1131-64-2
WeightAverage: 175.2303
Monoisotopic: 175.110947431
Chemical FormulaC10H13N3
InChI KeyInChIKey=JWPGJSVJDAJRLW-UHFFFAOYSA-N
InChI
InChI=1S/C10H13N3/c11-10(12)13-6-5-8-3-1-2-4-9(8)7-13/h1-4H,5-7H2,(H3,11,12)
IUPAC Name
1,2,3,4-tetrahydroisoquinoline-2-carboximidamide
SMILES
NC(=N)N1CCC2=CC=CC=C2C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassTetrahydroisoquinolines
Sub ClassNot Available
Direct ParentTetrahydroisoquinolines
Alternative Parents
Substituents
  • Tetrahydroisoquinoline
  • Benzenoid
  • Tertiary amine
  • Guanidine
  • Azacycle
  • Carboximidamide
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Imine
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension.
PharmacodynamicsDebrisoquin is an adrenergic neuron-blocking drug similar in effects to guanethidine. It is a substrate for a polymorphic cytochrome P-450 enzyme. Persons with certain isoforms of this enzyme are unable to properly metabolize this and many other clinically important drugs. They are commonly referred to as having a debrisoquin 4-hydroxylase polymorphism.
Mechanism of actionDebrisoquin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of norepinephrine, rather than acting at the effector cell by inhibiting the association of norepinephrine with its receptors. It is taken up by norepinephrine transporters. It becomes concentrated in NE transmitter vesicles, replacing NE in these vesicles. This leads to a gradual depletion of NE stores in the nerve endings. Once inside the terminal it blocks the release of noradrenaline in response to arrival of an action potential. In contrast to ganglionic blocking agents, debrisoquin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, debrisoquin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9714
Blood Brain Barrier+0.9106
Caco-2 permeable+0.5
P-glycoprotein substrateSubstrate0.8427
P-glycoprotein inhibitor INon-inhibitor0.8781
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterInhibitor0.8817
CYP450 2C9 substrateNon-substrate0.8429
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateNon-substrate0.7101
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9549
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.9532
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9462
Ames testNon AMES toxic0.7018
CarcinogenicityNon-carcinogens0.976
BiodegradationNot ready biodegradable0.9422
Rat acute toxicity2.7479 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6904
hERG inhibition (predictor II)Inhibitor0.5928
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point278-280 °CPhysProp
logP0.75SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.842 mg/mLALOGPS
logP0.58ALOGPS
logP1.07ChemAxon
logS-2.3ALOGPS
pKa (Strongest Basic)12.47ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area53.11 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity63.85 m3·mol-1ChemAxon
Polarizability19.48 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Wenner,W.; U.S. Patent 3,157,573; November 17,1964; assigned to Hoffmann-LaRoche, Inc.

General ReferencesNot Available
External Links
ATC CodesC02CC04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
References
  1. Joyce PI, Rizzi D, Calo G, Rowbotham DJ, Lambert DG: The effect of guanethidine and local anesthetics on the electrically stimulated mouse vas deferens. Anesth Analg. 2002 Nov;95(5):1339-43, table of contents. [PubMed:12401623 ]
  2. Bryan-Lluka LJ, Seers H, Sharpe I: Amezinium and debrisoquine are substrates of uptake1 and potent inhibitors of monoamine oxidase in perfused lungs of rats. Naunyn Schmiedebergs Arch Pharmacol. 1996 Apr;353(5):536-44. [PubMed:8740147 ]
  3. Mitchell JR, Cavanaugh JH, Arias L, Oates JA: Guanethidine and related agents. 3. Antagonism by drugs which inhibit the norepinephrine pump in man. J Clin Invest. 1970 Aug;49(8):1596-604. [PubMed:5431666 ]
  4. Yi E, Love JA: Alpha-adrenergic modulation of synaptic transmission in rabbit pancreatic ganglia. Auton Neurosci. 2005 Oct 30;122(1-2):45-57. Epub 2005 Aug 25. [PubMed:16126010 ]
  5. Galli A, Blakely RD, DeFelice LJ: Norepinephrine transporters have channel modes of conduction. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8671-6. [PubMed:8710929 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d 24-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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR: Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res. 1999 Mar;16(3):408-14. [PubMed:10213372 ]
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Drug created on September 26, 2007 09:28 / Updated on August 17, 2016 12:24