DROXIDOPA

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H11NO5
Molecular Weight	213.1877
Optical Activity	( - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

c1cc(c(cc1[C@]([H])([C@@]([H])(C(=O)O)N)O)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

HIDE SMILES / InChI

Molecular Formula	C9H11NO5
Molecular Weight	213.1877
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Adrenergic receptor beta 86 Target ID: CHEMBL2094118 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6124637	Agonist 2470	2600.0 nM [EC50]
Alpha-1a adrenergic receptor 64 Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26125514	Agonist 2470	9.1 nM [EC50]
Alpha-2a adrenergic receptor 62 Target ID: CHEMBL1867 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25282262	Agonist 2470	128.8 nM [EC50]
Alpha-2b adrenergic receptor 27 Target ID: CHEMBL1942 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476	Agonist 2470	61.7 nM [EC50]
Alpha-2c adrenergic receptor 37 Target ID: CHEMBL1916 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476	Agonist 2470	794.3 nM [EC50]
Adrenergic receptor 33 Target ID: CHEMBL2331074 Sources: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM292631.pdf	Agonist 2470

Conditions

Condition	Modality	Highest Phase	Product
Cardiac arrest 20 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdf	Primary	Approved 8043	LEVOPHED Approved Use INDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date -6.1447681E11
Hypotension 28 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdf	Primary	Approved 8043	LEVOPHED Approved Use INDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date -6.1447681E11
Systemic inflammatory response syndrome 8 Sources: https://clinicaltrials.gov/ct2/show/NCT02755155	Primary	Phase IV 63	LEVOPHED Approved Use INDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date -6.1447681E11
Neurogenic orthostatic hypotension 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf	Primary	Approved 8043	NORTHERA Approved Use Indicated 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 Date 1.39268155E12

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.4 min DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/007513s038lbl.pdf	unknown, intravenous		NOREPINEPHRINE unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
75% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/007513s038lbl.pdf	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: https://pubmed.ncbi.nlm.nih.gov/31490245/	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: https://pubmed.ncbi.nlm.nih.gov/31490245/	Other AEs: Mean arterial pressure high... Other AEs: Mean arterial pressure high (7.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/31490245/

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: https://pubmed.ncbi.nlm.nih.gov/31490245/	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: https://pubmed.ncbi.nlm.nih.gov/31490245/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
UGT1A1 192 UGT1A3 82 UGT2B7 141	SULT1A3 25 SERT 8 OCT3 75 OCT2 316

Drug as perpetrator

Target	Modality	Activity
UGT1A1 240	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: -	no
UGT1A3 91	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: -	no
UGT2B7 152	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: -	no

Drug as victim

Target	Modality	Activity
SULT1A3 25	substrate 3113 Sources: https://www.sciencedirect.com/science/article/pii/S0006295218300947 Page: -	yes [Km 10.65 uM]
OCT2 316	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/9687576/ Page: -	yes [Km 1900 uM]
OCT3 75	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/26432838/ Page: -	yes
SERT 8	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/27355037/ Page: -	yes

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B2-1645	http://www.3bsc.com/index/pro_info.php?id=55364
AA Blocks	AA01BHRG	https://www.aablocks.com/goods/Goods/detail?id=AA01BHRG
AHH Chemical co.,ltd	MT-00064	http://www.ahhchemical.com/product/MT-00064.html
Aaron Chemicals	AR01BIJ8	http://www.aaronchem.com/51-41-2
AbMole Bioscience	M9264	http://www.abmole.com/products/norepinephrine.html
Acadechem	ACDS-063951	http://www.acadechemical.com/product/138650
Achemo Scientific Limited	AC-11490	http://www.achemo.com/product_view.asp?ID=1380
Achemtek	0104-016514	http://www.achemtek.com/51-41-2
Alfa Aesar	L08087	https://www.alfa.com/en/catalog/L08087/
Alfa Chemistry	138-65-8	https://www.alfa-chemistry.com/cas_138-65-8.htm
Anward	ANW-74377	http://www.anward.com/pro_result/60828
Aurum Pharmatech LLC	C-4015	http://www.Aurumpharmatech.com/Product/ProductDetails/C_4015
BioSynth	W-105896	https://www.biosynth.com/en/products/chemical-intermediates/basic-intermediates/products/W-105896.html
Capot Chemical	6074	http://www.capotchem.com/en/6074.htm
Capot Chemical	PubChem6074	http://www.capotchem.com/en/6074.htm
Chem Scene	CS-0007744	http://www.chemscene.com/51-41-2.html
ChemFaces	CFN90047	http://www.chemfaces.com/natural/Norepinephrine-CFN90047.html
Chemenu	CM117224	http://www.chemenu.com/products/CM117224
Chemspace	CSSB00009815836	https://chem-space.com/CSSB00009815836
Clearsynth	CS-O-30989	http://www.clearsynth.com/en/CSO30989.html
Lab Network	LN00142026	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN00142026
Matrix Scientific	37592	https://www.matrixscientific.com/037592.html
MedChem Express	HY-13715	https://www.medchemexpress.com/Norepinephrine.html
MuseChem	I008327	https://www.musechem.com/product/I008327.html
OChem	4482	http://www.ocheminc.com/index.php?act=psearch&pid=025N592
Parchem	48632	https://www.parchem.com/chemical-supplier-distributor/L-Noradrenaline-048632.aspx
Selleck Chemicals	S9507	http://www.selleckchem.com/products/norepinephrine.html
Sigma-Aldrich	A7257_SIGMA	https://www.sigmaaldrich.com/catalog/product/sigma/a7257?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Sinfoo Biotech	S048294	http://www.sinfoobiotech.com/product/1051692
Smolecule	S537491	http://www.smolecule.com/products/s537491
Smolecule	S752210	https://www.smolecule.com/products/s752210
THE BioTek	bt-277557	https://www.thebiotek.com/product/inhibitors/bt-277557
THE BioTek	bt-299380	https://www.thebiotek.com/product/others/bt-299380
VladaChem	VL274159-1G	https://www.vladachem.com/product.php?products=51-41-2
abcr GmbH	AB178466	http://www.abcr.com/shop/en/AB178466
eNovation Chemicals	D675077	https://www.enovationchem.com/ProductDetails.asp?ProductID=D675077
iChemical	EBD153	http://www.ichemical.com/products/51-41-2.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs

PubMed

Title	Date	PubMed
Inhibition of protein phosphatase 1 induces apoptosis in neonatal rat cardiac myocytes: role of adrenergic receptor stimulation.	2000 Oct	11099166
Involvement of noradrenaline transporters in S-nitrosocysteine-stimulated noradrenaline release from rat brain slices: existence of functional Na(+)-independent transporter activity.	2001 Apr	11137627
Effect of dexmedetomidine on the release of [3H]-noradrenaline from rat kidney cortex slices: characterization of alpha2-adrenoceptor.	2001 Apr	11137626
alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P.	2001 Jan	11156594
Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize alpha(2)-adrenoceptors in the prefrontal cortex.	2001 Jan	11156576
Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes.	2001 Jan	11156573
Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes.	2001 Jan	11153756
Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension.	2001 Jan	11153742
Contrasting clinical properties and exercise responses in obese and lean hypertensive patients.	2001 Jan	11153733
Projections and pathways of VIP- and nNOS-containing airway neurons in ferret trachea.	2001 Jan	11152648
Arterial remodeling in chronic sinoaortic-denervated rats.	2001 Jan	11152375
Reversal of Haemorrhagic Shock in Rats by Tetrahydroaminoacridine.	2001 Jan	11150921
Modulatory effect of protein kinase C activator on contractility of rat vas deferens.	2001 Jan	11150916
Hormonal responses to exercise in chronic fatigue syndrome.	2001 Jan	11150897
Monoamine compounds in cerebrospinal fluid of healthy subjects punctured without preceding strict bed rest: a pilot study.	2001 Jan	11150891
Levels of circulating CD8(+) T lymphocytes, natural killer cells, and eosinophils increase upon acute psychosocial stress in patients with atopic dermatitis.	2001 Jan	11150008
Acute gastrointestinal manifestations associated with use of crack.	2001 Jan	11146022
N-methyl-D-aspartate receptors mediating hippocampal noradrenaline and striatal dopamine release display differential sensitivity to quinolinic acid, the HIV-1 envelope protein gp120, external pH and protein kinase C inhibition.	2001 Jan	11145986
Differences in central noradrenergic and behavioural responses of Maudsley non-reactive and Maudsley reactive inbred rats on exposure to an aversive novel environment.	2001 Jan	11145974
Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest.	2001 Jan	11136927
Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway.	2001 Jan	11135626
Efferent arteriole tubuloglomerular feedback in the renal nephron.	2001 Jan	11135074
Alteration of catecholamines in pheochromocytoma (PC12) cells in vitro by the metabolites of chlorotriazine herbicide.	2001 Jan	11134552
Effects of human pregnancy on cardiac autonomic function above and below the ventilatory threshold.	2001 Jan	11133925
Ventricular activation during sympathetic imbalance and its computational reconstruction.	2001 Jan	11133921
Dorsomedial medulla is more susceptible than rostral ventrolateral medulla to hypoxic insult in cats.	2001 Jan	11133917
Interaction of gender and exercise training: vasomotor reactivity of porcine skeletal muscle arteries.	2001 Jan	11133913
Catecholamine responses to alpha-adrenergic blockade during exercise in women acutely exposed to altitude.	2001 Jan	11133901
Catecholaminergic regulation of Na-K-Cl cotransport in pigmented ciliary epithelium: differences between PE and NPE.	2001 Jan	11133177
Neonatal catecholamine levels and neurodevelopmental outcome: a cohort study.	2001 Jan	11124926
In vitro reconstitution of fish melanophore pigment aggregation.	2001 Jan	11124706
A single bout of exercise induces beta-adrenergic desensitization in human adipose tissue.	2001 Jan	11124148
Substance P and NPY differentially potentiate ATP and adrenergic stimulated vasopressin and oxytocin release.	2001 Jan	11124136
Chronic type IV phosphodiesterase inhibition protects glomerular filtration rate and renal and mesenteric blood flow in a zymosan-induced model of multiple organ dysfunction syndrome treated with norepinephrine.	2001 Jan	11123377
Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction.	2001 Jan	11123195
Vasoactive intestinal peptide: cardiovascular effects.	2001 Jan	11121793
Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition.	2001 Jan 1	11150317
Potentiation by aminoethylisothiourea of the extra-cellular Ca(2+) component of norepinephrine-induced contraction in rat femoral arteries.	2001 Jan 1	11137715
Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring.	2001 Jan 1	11136866
Diacylglycerol kinase theta is translocated and phosphoinositide 3-kinase-dependently activated by noradrenaline but not angiotensin II in intact small arteries.	2001 Jan 1	11115406
The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat.	2001 Jan 12	11150485
Changes in sensitivity of cholinoceptors and adrenoceptors during transhemispheric cortical reorganisation in rat SmI.	2001 Jan 12	11150484
Nitric oxide synthase activity in peripheral polymorphonuclear leukocytes in patients with chronic congestive heart failure.	2001 Jan 15	11152836
Upregulation of immunoreactive angiotensin II release and angiotensinogen mRNA expression by high-frequency preganglionic stimulation at the canine cardiac sympathetic ganglia.	2001 Jan 19	11139482
Estrogen modulates norepinephrine-induced accumulation of adenosine cyclic monophosphate in a subpopulation of immortalized luteinizing hormone-releasing hormone secreting neurons from the mouse hypothalamus.	2001 Jan 26	11154836
A proposed pathological model in the hippocampus of subjects with schizophrenia.	2001 Jan-Feb	11153541
Effect of amlodipine on cardiopulmonary performance in volunteers.	2001 Jan-Feb	11153533
Dialysate dihydroxyphenylglycol as a window for in situ axoplasmic norepinephrine disposition.	2001 Mar	11099788
Low temperature prevents potentiation of norepinephrine release by phenylephrine.	2001 Mar	11099782
Determination of residues in the norepinephrine transporter that are critical for tricyclic antidepressant affinity.	2001 Mar 16	11092898

Patents

Sample Use Guides

In Vivo Use Guide

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

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 4C 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 `Fri Jun 25 21:21:17 UTC 2021` Edited by `admin` on `Fri Jun 25 21:21:17 UTC 2021`
Record UNII	J7A92W69L7
Record Status	`Validated (UNII)`
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Name

Type

Language

DROXIDOPA

Official Name

English

DROXIDOPA [INN]

Common Name

English

DOPS

Code

English

DROXIDOPA [VANDF]

Common Name

English

DROXIDOPA [WHO-DD]

Common Name

English

(-)-(2S,3R)-2-AMINO-3-(3,4-DIHYDROXYPHENYL)-3-HYDROXYPROPANOIC ACID

Systematic Name

English

DROXIDOPA [MI]

Common Name

English

DROXIDOPA [ORANGE BOOK]

Common Name

English

L-THREO-DOPS

Common Name

English

THREO-3,4-DIHYDROXYPHENYLSERINE, L-

Common Name

English

DROXIDOPA [USAN]

Common Name

English

L-TYROSINE, .BETA.,3-DIHYDROXY-, (.BETA.R)-

Common Name

English

NORTHERA

Brand Name

English

L-DOPS

Code

English

DROXIDOPA [JAN]

Common Name

English

DROXIDOPA [MART.]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

229506