Identification

Name
Droxidopa
Accession Number
DB06262
Type
Small Molecule
Groups
Approved, Investigational
Description

Droxidopa is a precursor of noradrenaline that is used in the treatment of Parkinsonism. It is approved for use in Japan and is currently in trials in the U.S. The racaemic form (dl-threo-3,4-dihydroxyphenylserine) has also been used, and has been investigated in the treatment of orthostatic hypotension. There is a deficit of noradrenaline as well as of dopamine in Parkinson's disease and it has been proposed that this underlies the sudden transient freezing seen usually in advanced disease.

Though L-DOPS has been used in Japan and Southeast Asia already for some time, it is also currently in clinical trials at the phase III point in the United States (U.S.), Canada, Australia, and throughout Europe. Provided L-DOPS successfully completes clinical trials, it could be approved for the treatment of neurogenic orthostatic hypotension (NOH) as early as 2011. Additionally, phase II clinical trials for intradialytic hypotension are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with Parkinson's disease , pure autonomic failure, and multiple system atrophy, and is the pharmaceutical company developing it in that country.

Structure
Thumb
Synonyms
  • DOPS
  • L-Dihydroxyphenylserine
  • L-DOPS
  • L-threo-dihydroxyphenylserine
External IDs
SM 5688 / SM-5688
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NortheraCapsule100 mg/1OralLundbeck Pharmaceuticals Llc2014-09-01Not applicableUs
NortheraCapsule100 mg/1OralChelsea Therapeutics Inc2014-02-182014-08-31Us
NortheraCapsule300 mg/1OralLundbeck Pharmaceuticals Llc2014-09-01Not applicableUs
NortheraCapsule300 mg/1OralChelsea Therapeutics Inc2014-08-312014-08-31Us
NortheraCapsule200 mg/1OralLundbeck Pharmaceuticals Llc2014-09-01Not applicableUs
NortheraCapsule200 mg/1OralChelsea Therapeutics Inc2014-08-312014-08-31Us
International/Other Brands
Dops
Categories
UNII
J7A92W69L7
CAS number
23651-95-8
Weight
Average: 213.189
Monoisotopic: 213.063722458
Chemical Formula
C9H11NO5
InChI Key
QXWYKJLNLSIPIN-JGVFFNPUSA-N
InChI
InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1
IUPAC Name
(2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
SMILES
N[C@@H]([C@H](O)C1=CC(O)=C(O)C=C1)C(O)=O

Pharmacology

Indication

For treatment of neurogenic orthostatic hypotension (NOH) associated with various disorders including Multiple System Atrophy, Familial Amyloid Polyneuropathy, hemodialysis induced hypotension and Parkinson's Disease. Also investigated for use/treatment in neurologic disorders, nephropathy, blood (blood forming organ disorders, unspecified), and dizzy/fainting spells.

Associated Conditions
Pharmacodynamics

Droxidopa is an orally active synthetic precursor of norepinephrine that increases the deficient supply of norepinephrine in patients with NOH, thereby improving orthostatic blood pressure and alleviating associated symptoms of lightheadedness, dizziness, blurred vision, and syncope through the induction of tachycardia (increased heart rate) and hypertension.

Mechanism of action

Droxidopa crosses the blood-brain barrier where it is converted to norepinephrine via decarboxylation by L-aromatic-amino-acid decarboxylase. Increased levels of norepinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Norephinephrine acts at alpha-adrenergic receptors as a vasoconstrictor and at beta-adrenergic receptors as a heart stimulator and artery dilator.

TargetActionsOrganism
AAlpha-1A adrenergic receptor
agonist
Human
AAlpha-1B adrenergic receptor
agonist
Human
AAlpha-1D adrenergic receptor
agonist
Human
AAlpha-2A adrenergic receptor
agonist
Human
AAlpha-2B adrenergic receptor
agonist
Human
AAlpha-2C adrenergic receptor
agonist
Human
ABeta-1 adrenergic receptor
agonist
Human
ABeta-2 adrenergic receptor
agonist
Human
ABeta-3 adrenergic receptor
agonist
Human
NPhenylalanine-4-hydroxylase
inhibitor
Human
Absorption

Oral bioavailability is 90%.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Droxidopa is metabolized by aromatic L-amino acid decarboxylase.

Route of elimination

Droxidopa is mainly excreted in the urine, with the main metabolite being 3-O-methyldihydroxyphenylserine.

Half life

2-3 hours.

Clearance
Not Available
Toxicity

Droxidopa has minimal toxic effects and an acute, oral LD50 of more than 5 g/kg in mice, rats, dogs, and monkeys. Side effects occur in in 0.78% of patients and include nausea, headache, increased blood pressure, hallucination, and anorexia.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
5-methoxy-N,N-dimethyltryptamine5-methoxy-N,N-dimethyltryptamine may increase the hypertensive activities of Droxidopa.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypertensive activities of Droxidopa.
AcebutololThe therapeutic efficacy of Droxidopa can be decreased when used in combination with Acebutolol.
AcepromazineAcepromazine may decrease the vasoconstricting activities of Droxidopa.
AcetaminophenAcetaminophen may decrease the excretion rate of Droxidopa which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Droxidopa which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Droxidopa which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Droxidopa which could result in a higher serum level.
AlclometasoneThe risk or severity of hypokalemia can be increased when Alclometasone is combined with Droxidopa.
AlfuzosinThe therapeutic efficacy of Droxidopa can be decreased when used in combination with Alfuzosin.
Food Interactions
Not Available

References

General References
  1. Kaufmann H: L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension: the US experience. Clin Auton Res. 2008 Mar;18 Suppl 1:19-24. doi: 10.1007/s10286-007-1002-2. Epub 2008 Mar 27. [PubMed:18368303]
  2. Balk SH, Yoshioka H, Yukawa H, Harayama S: Synthesis of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) with thermostabilized low-specific L-threonine aldolase from Streptomyces coelicolor A3(2). J Microbiol Biotechnol. 2007 May;17(5):721-7. [PubMed:18051291]
  3. Mathias CJ: L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. Clin Auton Res. 2008 Mar;18 Suppl 1:25-9. doi: 10.1007/s10286-007-1005-z. Epub 2008 Mar 27. [PubMed:18368304]
  4. Goldstein DS: L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. Cardiovasc Drug Rev. 2006 Fall-Winter;24(3-4):189-203. [PubMed:17214596]
  5. Goldstein DS, Holmes C, Kaufmann H, Freeman R: Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure. Clin Auton Res. 2004 Dec;14(6):363-8. [PubMed:15666063]
External Links
KEGG Drug
D01277
PubChem Compound
92974
PubChem Substance
99443239
ChemSpider
83927
ChEBI
31524
ChEMBL
CHEMBL2103827
PharmGKB
PA164748386
Wikipedia
Droxidopa
ATC Codes
C01CA27 — Droxidopa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentArterial Hypotension / Spinal Cord Injuries (SCI)1
1CompletedTreatmentQTc Interval1
1CompletedTreatmentSymptomatic Neurogenic Orthostatic Hypotension1
1RecruitingBasic ScienceAutonomic Failure / Idiopathic orthostatic hypotension / Multiple System Atrophy (MSA) / Parkinson's Disease (PD) / Progressive autonomic failure1
1WithdrawnTreatmentEnd Stage Renal Disease (ESRD) / Kidney Diseases1
1, 2TerminatedTreatmentAutonomic Nervous System Diseases / Multiple System Atrophy (MSA) / Parkinson's Disease (PD)1
1, 2TerminatedTreatmentOrthostatic Intolerance / Postural Orthostatic Tachycardia Syndrome (POTS)1
1, 2WithdrawnTreatmentGait Disorders, Neurologic1
2CompletedTreatmentAttention Deficit Disorder With Hyperactivity (ADHD)1
2CompletedTreatmentFibromyalgia1
2CompletedTreatmentIntradialytic Hypotension1
2Enrolling by InvitationTreatmentCognitive Ability, General / Freezing of Gait / Parkinson's Disease (PD)1
2Not Yet RecruitingTreatmentMultiple System Atrophy (MSA) / Parkinson's Disease (PD) / Progressive Supranuclear Palsy (PSP)1
2RecruitingTreatmentFalls Patient / Parkinson's Disease (PD)1
2RecruitingTreatmentParkinson's Disease (PD)1
2RecruitingTreatmentPostural Tachycardia Syndrome (POTS) / Syncope / Vasovagal Syncope (VVS)1
2RecruitingTreatmentIdiopathic orthostatic hypotension1
2TerminatedTreatmentIdiopathic orthostatic hypotension / Myalgic Encephalomyelitis (ME) / Neurally Mediated Hypotension / Neurogenic Orthostatic Hypotension1
2WithdrawnTreatmentHSAN Type IV1
3CompletedTreatmentDopamine Beta Hydroxylase Deficiency / Multiple System Atrophy (MSA) / Neurogenic Orthostatic Hypotension / Non-Diabetic Autonomic Neuropathy1
3CompletedTreatmentDopamine Beta Hydroxylase Deficiency / Neurogenic Orthostatic Hypotension / Non-Diabetic Neuropathy / Primary Autonomic Failure1
3CompletedTreatmentDopamine Beta Hydroxylase Deficiency / Non-Diabetic Neuropathy / Primary Autonomic Failure / Symptomatic Neurogenic Orthostatic Hypotension (NOH)2
3CompletedTreatmentIdiopathic orthostatic hypotension / Parkinson's Disease (PD)1
3Enrolling by InvitationTreatmentAutonomic Nervous System Diseases / Dopamine Beta-Hydroxylase Deficiency / Idiopathic orthostatic hypotension / Orthostatic Intolerance1
3TerminatedTreatmentDopamine Beta Hydroxylase Deficiency / Multiple Systems Atrophy / Parkinson's Disease (PD) / Progressive autonomic failure / Symptomatic Neurogenic Orthostatic Hypotension1
3TerminatedTreatmentIdiopathic orthostatic hypotension1
4RecruitingTreatmentArterial Hypotension / Idiopathic orthostatic hypotension / Spinal Cord Injuries (SCI)1
4RecruitingTreatmentNeurogenic Orthostatic Hypotension / Parkinson's Disease (PD)1
4RecruitingTreatmentParkinson's Disease (PD)1
4RecruitingTreatmentParkinson's Disease (PD) / Parkinsonism / Tiredness1
4RecruitingTreatmentSymptomatic Neurogenic Orthostatic Hypotension1
Not AvailableApproved for MarketingNot AvailableDopamine Beta Hydroxylase (DBH) Deficiency1
Not AvailableCompletedTreatmentParkinson's Disease (PD)1
Not AvailableCompletedTreatmentIdiopathic orthostatic hypotension / Shy-Drager Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral200 mg/1
CapsuleOral300 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility15.3 mg/mLALOGPS
logP-2.4ALOGPS
logP-2.7ChemAxon
logS-1.1ALOGPS
pKa (Strongest Acidic)1.46ChemAxon
pKa (Strongest Basic)8.72ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area124.01 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity50.29 m3·mol-1ChemAxon
Polarizability19.85 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8412
Blood Brain Barrier-0.9305
Caco-2 permeable-0.8613
P-glycoprotein substrateNon-substrate0.7167
P-glycoprotein inhibitor INon-inhibitor0.9874
P-glycoprotein inhibitor IINon-inhibitor0.993
Renal organic cation transporterNon-inhibitor0.949
CYP450 2C9 substrateNon-substrate0.8401
CYP450 2D6 substrateNon-substrate0.8805
CYP450 3A4 substrateNon-substrate0.7587
CYP450 1A2 substrateNon-inhibitor0.8012
CYP450 2C9 inhibitorNon-inhibitor0.9573
CYP450 2D6 inhibitorNon-inhibitor0.9472
CYP450 2C19 inhibitorNon-inhibitor0.8565
CYP450 3A4 inhibitorNon-inhibitor0.76
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9562
Ames testNon AMES toxic0.7494
CarcinogenicityNon-carcinogens0.9262
BiodegradationReady biodegradable0.765
Rat acute toxicity1.3600 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9904
hERG inhibition (predictor II)Non-inhibitor0.9693
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 tyrosine and derivatives. These are compounds containing tyrosine or a derivative thereof resulting from reaction of tyrosine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Tyrosine and derivatives
Alternative Parents
Phenylalanine and derivatives / Phenylpropanoic acids / L-alpha-amino acids / Catechols / 1-hydroxy-2-unsubstituted benzenoids / 1-hydroxy-4-unsubstituted benzenoids / Aralkylamines / Beta hydroxy acids and derivatives / Benzene and substituted derivatives / Secondary alcohols
show 9 more
Substituents
Tyrosine or derivatives / Phenylalanine or derivatives / 3-phenylpropanoic-acid / Alpha-amino acid / L-alpha-amino acid / Catechol / Beta-hydroxy acid / 1-hydroxy-2-unsubstituted benzenoid / Aralkylamine / 1-hydroxy-4-unsubstituted benzenoid
show 22 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
L-tyrosine derivative, catechol (CHEBI:31524)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Senard JM, Brefel-Courbon C, Rascol O, Montastruc JL: Orthostatic hypotension in patients with Parkinson's disease: pathophysiology and management. Drugs Aging. 2001;18(7):495-505. [PubMed:11482743]
  2. Bishop MJ: Recent advances in the discovery of alpha1-adrenoceptor agonists. Curr Top Med Chem. 2007;7(2):135-45. [PubMed:17266602]
  3. Du L, Li M: Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists. Curr Comput Aided Drug Des. 2010 Sep;6(3):165-78. [PubMed:20412040]
  4. Lachnit WG, Tran AM, Clarke DE, Ford AP: Pharmacological characterization of an alpha 1A-adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat. Br J Pharmacol. 1997 Mar;120(5):819-26. [PubMed:9138687]
  5. Burt RP, Chapple CR, Marshall I: The role of diacylglycerol and activation of protein kinase C in alpha 1A-adrenoceptor-mediated contraction to noradrenaline of rat isolated epididymal vas deferens. Br J Pharmacol. 1996 Jan;117(1):224-30. [PubMed:8825367]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Bishop MJ: Recent advances in the discovery of alpha1-adrenoceptor agonists. Curr Top Med Chem. 2007;7(2):135-45. [PubMed:17266602]
  2. Du L, Li M: Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists. Curr Comput Aided Drug Des. 2010 Sep;6(3):165-78. [PubMed:20412040]
  3. Testa R, Guarneri L, Poggesi E, Simonazzi I, Taddei C, Leonardi A: Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype. Br J Pharmacol. 1995 Feb;114(4):745-50. [PubMed:7773533]
  4. Izzo NJ Jr, Colucci WS: Regulation of alpha 1B-adrenergic receptor half-life: protein synthesis dependence and effect of norepinephrine. Am J Physiol. 1994 Mar;266(3 Pt 1):C771-5. [PubMed:8166240]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
References
  1. Bishop MJ: Recent advances in the discovery of alpha1-adrenoceptor agonists. Curr Top Med Chem. 2007;7(2):135-45. [PubMed:17266602]
  2. Du L, Li M: Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists. Curr Comput Aided Drug Des. 2010 Sep;6(3):165-78. [PubMed:20412040]
  3. Kenny BA, Chalmers DH, Philpott PC, Naylor AM: Characterization of an alpha 1D-adrenoceptor mediating the contractile response of rat aorta to noradrenaline. Br J Pharmacol. 1995 Jul;115(6):981-6. [PubMed:7582530]
  4. Testa R, Destefani C, Guarneri L, Poggesi E, Simonazzi I, Taddei C, Leonardi A: The alpha 1d-adrenoceptor subtype is involved in the noradrenaline-induced contractions of rat aorta. Life Sci. 1995;57(13):PL159-63. [PubMed:7674815]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Davis MP: Recent advances in the treatment of pain. F1000 Med Rep. 2010 Aug 19;2:63. doi: 10.3410/M2-63. [PubMed:21173850]
  2. Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V: Alpha2-agonists as analgesic agents. Med Res Rev. 2009 Mar;29(2):339-68. doi: 10.1002/med.20134. [PubMed:18680204]
  3. Nyronen T, Pihlavisto M, Peltonen JM, Hoffren AM, Varis M, Salminen T, Wurster S, Marjamaki A, Kanerva L, Katainen E, Laaksonen L, Savola JM, Scheinin M, Johnson MS: Molecular mechanism for agonist-promoted alpha(2A)-adrenoceptor activation by norepinephrine and epinephrine. Mol Pharmacol. 2001 May;59(5):1343-54. [PubMed:11306720]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Epinephrine binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine...
Gene Name
ADRA2B
Uniprot ID
P18089
Uniprot Name
Alpha-2B adrenergic receptor
Molecular Weight
49565.8 Da
References
  1. Davis MP: Recent advances in the treatment of pain. F1000 Med Rep. 2010 Aug 19;2:63. doi: 10.3410/M2-63. [PubMed:21173850]
  2. Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V: Alpha2-agonists as analgesic agents. Med Res Rev. 2009 Mar;29(2):339-68. doi: 10.1002/med.20134. [PubMed:18680204]
  3. Gilsbach R, Hein L: Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline. Handb Exp Pharmacol. 2008;(184):261-88. [PubMed:18064417]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Gene Name
ADRA2C
Uniprot ID
P18825
Uniprot Name
Alpha-2C adrenergic receptor
Molecular Weight
49521.585 Da
References
  1. Davis MP: Recent advances in the treatment of pain. F1000 Med Rep. 2010 Aug 19;2:63. doi: 10.3410/M2-63. [PubMed:21173850]
  2. Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V: Alpha2-agonists as analgesic agents. Med Res Rev. 2009 Mar;29(2):339-68. doi: 10.1002/med.20134. [PubMed:18680204]
  3. Rump LC, Bohmann C, Schaible U, Schollhorn J, Limberger N: Alpha 2C-adrenoceptor-modulated release of noradrenaline in human right atrium. Br J Pharmacol. 1995 Nov;116(6):2617-24. [PubMed:8590979]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor signaling protein activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately e...
Gene Name
ADRB1
Uniprot ID
P08588
Uniprot Name
Beta-1 adrenergic receptor
Molecular Weight
51322.1 Da
References
  1. Mersmann HJ: Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci. 1998 Jan;76(1):160-72. [PubMed:9464897]
  2. El-Armouche A, Eschenhagen T: Beta-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev. 2009 Dec;14(4):225-41. doi: 10.1007/s10741-008-9132-8. [PubMed:19110970]
  3. Gilsbach R, Hein L: Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline. Handb Exp Pharmacol. 2008;(184):261-88. [PubMed:18064417]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately ...
Gene Name
ADRB2
Uniprot ID
P07550
Uniprot Name
Beta-2 adrenergic receptor
Molecular Weight
46458.32 Da
References
  1. Mersmann HJ: Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci. 1998 Jan;76(1):160-72. [PubMed:9464897]
  2. Sanders VM: The role of norepinephrine and beta-2-adrenergic receptor stimulation in the modulation of Th1, Th2, and B lymphocyte function. Adv Exp Med Biol. 1998;437:269-78. [PubMed:9666280]
  3. Tarizzo VI, Coppes RP, Dahlof C, Zaagsma J: Pre- and postganglionic stimulation-induced noradrenaline overflow is markedly facilitated by a prejunctional beta 2-adrenoceptor-mediated control mechanism in the pithed rat. Naunyn Schmiedebergs Arch Pharmacol. 1994 Jun;349(6):570-7. [PubMed:7969507]
  4. El-Armouche A, Eschenhagen T: Beta-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev. 2009 Dec;14(4):225-41. doi: 10.1007/s10741-008-9132-8. [PubMed:19110970]
  5. Gilsbach R, Hein L: Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline. Handb Exp Pharmacol. 2008;(184):261-88. [PubMed:18064417]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.
Gene Name
ADRB3
Uniprot ID
P13945
Uniprot Name
Beta-3 adrenergic receptor
Molecular Weight
43518.615 Da
References
  1. Coman OA, Paunescu H, Ghita I, Coman L, Badararu A, Fulga I: Beta 3 adrenergic receptors: molecular, histological, functional and pharmacological approaches. Rom J Morphol Embryol. 2009;50(2):169-79. [PubMed:19434307]
  2. Mersmann HJ: Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci. 1998 Jan;76(1):160-72. [PubMed:9464897]
  3. El-Armouche A, Eschenhagen T: Beta-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev. 2009 Dec;14(4):225-41. doi: 10.1007/s10741-008-9132-8. [PubMed:19110970]
  4. Gilsbach R, Hein L: Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline. Handb Exp Pharmacol. 2008;(184):261-88. [PubMed:18064417]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Phenylalanine 4-monooxygenase activity
Specific Function
Not Available
Gene Name
PAH
Uniprot ID
P00439
Uniprot Name
Phenylalanine-4-hydroxylase
Molecular Weight
51861.565 Da
References
  1. Martinez A, Andersson KK, Haavik J, Flatmark T: EPR and 1H-NMR spectroscopic studies on the paramagnetic iron at the active site of phenylalanine hydroxylase and its interaction with substrates and inhibitors. Eur J Biochem. 1991 Jun 15;198(3):675-82. [PubMed:1646718]
  2. Martinez A, Haavik J, Flatmark T: Cooperative homotropic interaction of L-noradrenaline with the catalytic site of phenylalanine 4-monooxygenase. Eur J Biochem. 1990 Oct 5;193(1):211-9. [PubMed:2226440]
  3. Molinoff PB: The regulation of the noradrenergic neuron. J Psychiatr Res. 1974;11:339-45. [PubMed:4156788]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Pyridoxal phosphate binding
Specific Function
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine.
Gene Name
DDC
Uniprot ID
P20711
Uniprot Name
Aromatic-L-amino-acid decarboxylase
Molecular Weight
53925.815 Da
References
  1. Goldstein DS: L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. Cardiovasc Drug Rev. 2006 Fall-Winter;24(3-4):189-203. [PubMed:17214596]
  2. Maruyama W, Naoi M, Narabayashi H: [The effect of droxidopa on the monoamine metabolsim in the human brain]. Rinsho Shinkeigaku. 1994 Oct;34(10):985-90. [PubMed:7834959]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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. Habecker BA, Willison BD, Shi X, Woodward WR: Chronic depolarization stimulates norepinephrine transporter expression via catecholamines. J Neurochem. 2006 May;97(4):1044-51. Epub 2006 Mar 29. [PubMed:16573647]
  2. Bonisch H, Bruss M: The norepinephrine transporter in physiology and disease. Handb Exp Pharmacol. 2006;(175):485-524. [PubMed:16722247]
  3. Mandela P, Ordway GA: KCl stimulation increases norepinephrine transporter function in PC12 cells. J Neurochem. 2006 Sep;98(5):1521-30. Epub 2006 Jul 31. [PubMed:16879714]
  4. Gutman DA, Owens MJ: Serotonin and norepinephrine transporter binding profile of SSRIs. Essent Psychopharmacol. 2006;7(1):35-41. [PubMed:16989291]
  5. Ksiazek P, Buraczynska K, Buraczynska M: Norepinephrine transporter gene (NET) polymorphism in patients with type 2 diabetes. Kidney Blood Press Res. 2006;29(6):338-43. Epub 2006 Nov 23. [PubMed:17124432]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Sodium-independent transporter that mediates the update of aromatic acid. Can function as a net efflux pathway for aromatic amino acids in the basosolateral epithelial cells (By similarity).
Gene Name
SLC16A10
Uniprot ID
Q8TF71
Uniprot Name
Monocarboxylate transporter 10
Molecular Weight
55492.07 Da
References
  1. Kim DK, Kanai Y, Chairoungdua A, Matsuo H, Cha SH, Endou H: Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters. J Biol Chem. 2001 May 18;276(20):17221-8. Epub 2001 Feb 20. [PubMed:11278508]

Drug created on March 19, 2008 10:20 / Updated on October 01, 2018 14:06