Identification

Name
Debrisoquin
Accession Number
DB04840
Type
Small Molecule
Groups
Approved, Investigational
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
Product Ingredients
IngredientUNIICASInChI Key
Debrisoquin sulfateQ94064N9NW581-88-4CAYGYVYWRIHZCQ-UHFFFAOYSA-N
International/Other Brands
Bonipress (lkapharm) / Declinax (Roche) / Tendor (Chinoin)
Categories
UNII
X31CDK040E
CAS number
1131-64-2
Weight
Average: 175.2303
Monoisotopic: 175.110947431
Chemical Formula
C10H13N3
InChI Key
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

Pharmacology

Indication

For the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension.

Pharmacodynamics

Debrisoquin 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 action

Debrisoquin 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.

TargetActionsOrganism
ASodium-dependent noradrenaline transporter
inducer
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may increase the hypotensive activities of Debrisoquin.
4-MethoxyamphetamineThe metabolism of Debrisoquin can be decreased when combined with 4-Methoxyamphetamine.
AbataceptThe metabolism of Debrisoquin can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Debrisoquin can be increased when it is combined with Abemaciclib.
AbirateroneThe metabolism of Debrisoquin can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Debrisoquin can be decreased when combined with Acebutolol.
AceclofenacThe therapeutic efficacy of Debrisoquin can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Debrisoquin can be decreased when used in combination with Acemetacin.
AcetaminophenThe serum concentration of Debrisoquin can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe therapeutic efficacy of Debrisoquin can be decreased when used in combination with Acetylsalicylic acid.
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference

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

General References
Not Available
External Links
Human Metabolome Database
HMDB0006543
KEGG Compound
C13650
PubChem Compound
2966
PubChem Substance
46507664
ChemSpider
2860
BindingDB
50122613
ChEBI
34665
ChEMBL
CHEMBL169901
Therapeutic Targets Database
DAP000125
PharmGKB
PA452616
Wikipedia
Debrisoquine
ATC Codes
C02CC04 — Debrisoquine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableRecruitingOtherHealthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)278-280 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
Not Available
Direct Parent
Tetrahydroisoquinolines
Alternative Parents
Benzenoids / Guanidines / Carboximidamides / Azacyclic compounds / Organopnictogen compounds / Imines / Hydrocarbon derivatives
Substituents
Tetrahydroisoquinoline / Benzenoid / Guanidine / Azacycle / Carboximidamide / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative / Organonitrogen compound / Imine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
carboxamidine, isoquinolines (CHEBI:34665)

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
Uniprot Name
Sodium-dependent noradrenaline transporter
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

Details
1. Cytochrome P450 2D6
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
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 un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
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
Uniprot Name
Multidrug resistance protein 1
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]

Drug created on September 26, 2007 09:28 / Updated on December 14, 2018 05:38