Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C9H11NO5 |
Molecular Weight | 213.1873 |
Optical Activity | ( - ) |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
N[C@@H]([C@H](O)C1=CC(O)=C(O)C=C1)C(O)=O
InChI
InChIKey=QXWYKJLNLSIPIN-JGVFFNPUSA-N
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
Molecular Formula | C9H11NO5 |
Molecular Weight | 213.1873 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdfCurator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=17214596; http://www.ncbi.nlm.nih.gov/pubmed/?term=18368304
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=17214596; http://www.ncbi.nlm.nih.gov/pubmed/?term=18368304
Droxidopa (Northera, Chelsea Therapeutics) is a synthetic catecholamino acid precursor of norepinephrine indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa was approved as oral therapy in February 2014 under the FDA’s accelerated approval program. Droxidopa is directly metabolized to norepinephrine by dopadecarboxylase. The specific mechanism of action of the drug is not known completely, but it is supposed to exert the pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. It increases blood flow to the brain by stimulating peripheral arterial and venous vasoconstriction.
CNS Activity
Sources: http://www.caam.rice.edu/~cox/wrap/norepinephrine.pdfhttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM292631.pdf
Curator's Comment: Droxidopa, a prodrug, is converted mostly peripherally, but also centrally (as it passes through the blood brain barrier) into norepinephrine (NE).
Originator
Sources: Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales (1932), 111, 884-6.http://www.businesswire.com/news/home/20140218006891/en/Chelsea-Therapeutics-Announces-FDA-Accelerated-Approval-NORTHERA%E2%84%A2
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2094118 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6124637 |
2600.0 nM [EC50] | ||
Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26125514 |
9.1 nM [EC50] | ||
Target ID: CHEMBL1867 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25282262 |
128.8 nM [EC50] | ||
Target ID: CHEMBL1942 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476 |
61.7 nM [EC50] | ||
Target ID: CHEMBL1916 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476 |
794.3 nM [EC50] | ||
Target ID: CHEMBL2331074 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | NORTHERA Approved UseIndicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure [Parkinson's disease (PD), multiple system atrophy and pure autonomic failure], dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Launch Date2014 |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.4 min |
unknown, intravenous |
NOREPINEPHRINE unknown | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
75% |
unknown, intravenous |
NOREPINEPHRINE unknown | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
0.6 ug/kg/min single, intravenous Highest studied dose Dose: 0.6 ug/kg/min Route: intravenous Route: single Dose: 0.6 ug/kg/min Sources: |
unhealthy, mean 65.5 years n = 85 Health Status: unhealthy Condition: cardiogenic shock Age Group: mean 65.5 years Sex: M+F Population Size: 85 Sources: |
Other AEs: Mean arterial pressure high... |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Mean arterial pressure high | 7.2% | 0.6 ug/kg/min single, intravenous Highest studied dose Dose: 0.6 ug/kg/min Route: intravenous Route: single Dose: 0.6 ug/kg/min Sources: |
unhealthy, mean 65.5 years n = 85 Health Status: unhealthy Condition: cardiogenic shock Age Group: mean 65.5 years Sex: M+F Population Size: 85 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: - |
yes [Km 10.65 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9687576/ Page: - |
yes [Km 1900 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/26432838/ Page: - |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/27355037/ Page: - |
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Vasopressor agents in shock. | 1975 Apr |
|
Electrophysiologic studies in the denervated transplanted human heart. II. Response to norepinephrine, isoproterenol and propranolol. | 1975 Dec |
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Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. | 1999 Apr |
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Microphysiometric analysis of human alpha1a-adrenoceptor expressed in Chinese hamster ovary cells. | 1999 Jun |
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Does acute volume overloading in the setting of left ventricular dysfunction and pulmonary hypertension affect the defibrillation threshold? | 1999 May |
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[Distributive shock and it's therapy by cardio-vascular acting drugs]. | 1999 Oct |
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[Hypotension refractory to ephedrine after sympathetic blockade in a patient on long-term therapy with tricyclic antidepressants]. | 1999 Oct |
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Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a beta -adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. | 2000 May 5 |
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Comitogenic effect of catecholamines on rat cardiac fibroblasts in culture. | 2000 Nov |
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Near fatal case of atrio-ventricular block induced by amitriptyline at therapeutic dose. | 2000 Sep |
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Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization. | 2001 Feb 16 |
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Arterial remodeling in chronic sinoaortic-denervated rats. | 2001 Jan |
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Reversal of Haemorrhagic Shock in Rats by Tetrahydroaminoacridine. | 2001 Jan |
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Modulatory effect of protein kinase C activator on contractility of rat vas deferens. | 2001 Jan |
|
Hormonal responses to exercise in chronic fatigue syndrome. | 2001 Jan |
|
Monoamine compounds in cerebrospinal fluid of healthy subjects punctured without preceding strict bed rest: a pilot study. | 2001 Jan |
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Ventricular activation during sympathetic imbalance and its computational reconstruction. | 2001 Jan |
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Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. | 2001 Jan |
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The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. | 2001 Jan |
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Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion. | 2001 Jan |
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A single bout of exercise induces beta-adrenergic desensitization in human adipose tissue. | 2001 Jan |
|
Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting. | 2001 Jan |
|
Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. | 2001 Jan |
|
Neuroendocrine responses to experimentally-induced psychological stress in healthy humans. | 2001 Jan |
|
Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. | 2001 Jan 1 |
|
Potentiation by aminoethylisothiourea of the extra-cellular Ca(2+) component of norepinephrine-induced contraction in rat femoral arteries. | 2001 Jan 1 |
|
IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. | 2001 Jan 1 |
|
Effect of amlodipine on cardiopulmonary performance in volunteers. | 2001 Jan-Feb |
|
Low temperature prevents potentiation of norepinephrine release by phenylephrine. | 2001 Mar |
|
Determination of residues in the norepinephrine transporter that are critical for tricyclic antidepressant affinity. | 2001 Mar 16 |
Patents
Sample Use Guides
Acute Hypotension. Initial: 8-12 mcg/min IV infusion; titrate to effect; Maintenance: 2-4 mcg/min IV infusion
Cardiac Arrest. Initial: 8-12 mcg/min IV infusion; titrate to effect; Maintenance: 2-4 mcg/min IV infusion
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27650061
Human umbilical vein endothelial cell line (ECV-304, Shanghai Institute of Cell Biology, Chinese Academy of Science) were used for activity evaluation. Cells were conventionally cultured with modified alpha-MEM containing 10% fetal bovine serum Before all the manipulation experiments, the ECV-304 (VECs) were shifted to serum-free medium (normal medium) and then divided into three groups as follows. Control group was cultured in normal medium in which 0 mol/L NE (Norepinephrine) was detecteded using the NE ELISA kit. NE+Inhibitor group was cultured in normal medium added with 10^-7 mol/L NE (Harcest Pharmaceutical CO,. Shanghai, China) and NE blocker Amitriptyline hydrochloride (10-6 mol/L). NE+Isotype group was cultured in normal medium added with 10^-7 mol/L NE (Norepinephrine) and a negative isotype of NE blocker Amitriptyline hydrochloride. The dose of NE utilized in the experiments was determined in advance through titration. It was selected to approximate the normal concentration in vivo. After 24 h of culture, the supernatant from each group was collected to measure SDF-1 using an ELISA kit (Human CXCL12/SDF-1 alpha Quantikine ELISA Kit; R&D Systems, USA) according to the manufacturer’s protocol. Similarly, the cells from the cell culture were collected for Western blotting analysis. First, proteins were extracted from the cells using the M-PER mammalian protein extraction reagent (Thermo Fisher Scientific, Hudson, USA). Then, the proteins were resolved on a NuPAGE gel and transferred to nylon membranes. After blocking with 7% fat-free dry milk for 2 h, the membranes were incubated with polyclonal rabbit anti-human SDF-1, JNK or p-JNK antibodies (1:200; Santa Cruz) at 4C overnight. After incubation with horseradish peroxidase-conjugated IgG (Santa Cruz) for 1 h, the membranes were treated with chemiluminescent substrate (Thermo) to visualize the protein bands.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 17:01:18 GMT 2023
by
admin
on
Sat Dec 16 17:01:18 GMT 2023
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Record UNII |
J7A92W69L7
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Record Status |
Validated (UNII)
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Record Version |
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
229506
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EU-Orphan Drug |
EU/3/07/465
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WHO-ATC |
C01CA27
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EU-Orphan Drug |
EU/3/07/466
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NCI_THESAURUS |
C38149
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UU-114
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971
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J7A92W69L7
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L-DOPS
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D015103
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60568
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C73266
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1489913
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100000081029
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DTXSID6046422
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N0000178478
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PRIMARY | Increased Blood Pressure [PE] | ||
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23651-95-8
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7391
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J7A92W69L7
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CHEMBL2103827
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92974
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DB06262
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SUB06420MIG
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m4774
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PRIMARY | Merck Index | ||
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6120
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31524
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Related Record | Type | Details | ||
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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BINDER->LIGAND |
BINDING
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TARGET -> AGONIST |
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METABOLIC ENZYME -> SUBSTRATE |
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RACEMATE -> ENANTIOMER |
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METABOLIC ENZYME -> SUBSTRATE |
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TARGET -> INHIBITOR |
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TARGET -> INHIBITOR |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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Related Record | Type | Details | ||
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
MAJOR
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METABOLITE -> PARENT |
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METABOLITE ACTIVE -> PRODRUG |
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
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ACTIVE MOIETY |
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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