Basic Info

Common NameMethyldopa(F04861)
2D Structure
Description

Methyldopa or alpha-methyldopa (brand names Aldomet, Apo-Methyldopa, Dopamet, Novomedopa) is a centrally-acting adrenergic antihypertensive medication. Its use is now deprecated following introduction of alternative safer classes of agents. However it continues to have a role in otherwise difficult to treat hypertension and gestational hypertension (formerly known as pregnancy-induced hypertension). Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Only methyldopa, the <i>L</i>-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect. Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed. Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy. Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur. Methyldopa, in its active metabolite form, is a central alpha-2 receptor agonist. Using methyldopa leads to alpha-2 receptor-negative feedback to sympathetic nervous system (SNS) (centrally and peripherally), allowing peripheral sympathetic nervous system tone to decrease. Such activity leads to a decrease in total peripheral resistance (TPR) and cardiac output. When introduced it was a mainstay of antihypertensive therapy, but its use has declined, with increased use of other safer classes of agents. One of its important present-day uses is in the management of pregnancy-induced hypertension, as it is relatively safe in pregnancy compared to other antihypertensive drugs (Wikipedia).

FRCD IDF04861
CAS Number555-30-6
PubChem CID38853
FormulaC10H13NO4
IUPAC Name

(2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid

InChI Key

CJCSPKMFHVPWAR-JTQLQIEISA-N

InChI

InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1

Canonical SMILES

CC(CC1=CC(=C(C=C1)O)O)(C(=O)O)N

Isomeric SMILES

C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N

WikipediaMethyldopa
Synonyms
        
            l-alpha-Methyldopa
        
            methyldopa
        
            555-30-6
        
            Alphamethyldopa
        
            Aldomet
        
            Alpha medopa
        
            Dopamet
        
            alpha-Methyl dopa
        
            Baypresol
        
            Hyperpax
        
Classifies
                

                  
                    Predicted: Animal Toxin
                  

                
        
Update DateNov 13, 2018 17:07

Chemical Taxonomy

KingdomOrganic compounds
SuperclassPhenylpropanoids and polyketides
ClassPhenylpropanoic acids
SubclassNot available
Intermediate Tree NodesNot available
Direct ParentPhenylpropanoic acids
Alternative Parents
Molecular FrameworkAromatic homomonocyclic compounds
Substituents3-phenylpropanoic-acid - Alpha-amino acid - D-alpha-amino acid - Alpha-amino acid or derivatives - Amphetamine or derivatives - Phenylpropane - Catechol - 1-hydroxy-2-unsubstituted benzenoid - Aralkylamine - 1-hydroxy-4-unsubstituted benzenoid - Phenol - Monocyclic benzene moiety - Benzenoid - Amino acid - Amino acid or derivatives - Carboxylic acid derivative - Monocarboxylic acid or derivatives - Carboxylic acid - Organic nitrogen compound - Primary aliphatic amine - Organonitrogen compound - Organooxygen compound - Primary amine - Carbonyl group - Hydrocarbon derivative - Organic oxide - Organopnictogen compound - Amine - Organic oxygen compound - Aromatic homomonocyclic compound
DescriptionThis compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.

Properties

Property NameProperty Value
Molecular Weight211.217
Hydrogen Bond Donor Count4
Hydrogen Bond Acceptor Count5
Rotatable Bond Count3
Complexity246
Monoisotopic Mass211.084
Exact Mass211.084
XLogP-1.9
Formal Charge0
Heavy Atom Count15
Defined Atom Stereocenter Count1
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Isotope Atom Count0
Covalently-Bonded Unit Count1

ADMET

Model Result Probability
Absorption
Blood-Brain BarrierBBB-0.9276
Human Intestinal AbsorptionHIA+0.9374
Caco-2 PermeabilityCaco2-0.8957
P-glycoprotein SubstrateSubstrate0.6066
P-glycoprotein InhibitorNon-inhibitor0.9852
Non-inhibitor0.9895
Renal Organic Cation TransporterNon-inhibitor0.9357
Distribution
Subcellular localizationMitochondria0.4823
Metabolism
CYP450 2C9 SubstrateNon-substrate0.7757
CYP450 2D6 SubstrateNon-substrate0.8000
CYP450 3A4 SubstrateNon-substrate0.6053
CYP450 1A2 InhibitorNon-inhibitor0.9045
CYP450 2C9 InhibitorNon-inhibitor0.9369
CYP450 2D6 InhibitorNon-inhibitor0.9491
CYP450 2C19 InhibitorNon-inhibitor0.9233
CYP450 3A4 InhibitorNon-inhibitor0.8640
CYP Inhibitory PromiscuityLow CYP Inhibitory Promiscuity0.9551
Excretion
Toxicity
Human Ether-a-go-go-Related Gene InhibitionWeak inhibitor0.9939
Non-inhibitor0.9629
AMES ToxicityNon AMES toxic0.8185
CarcinogensNon-carcinogens0.8997
Fish ToxicityHigh FHMT0.8770
Tetrahymena Pyriformis ToxicityHigh TPT0.7375
Honey Bee ToxicityLow HBT0.6296
BiodegradationNot ready biodegradable0.8077
Acute Oral ToxicityIV0.6203
Carcinogenicity (Three-class)Non-required0.7090

Model Value Unit
Absorption
Aqueous solubility-1.8784LogS
Caco-2 Permeability-0.3080LogPapp, cm/s
Distribution
Metabolism
Excretion
Toxicity
Rat Acute Toxicity1.6281LD50, mol/kg
Fish Toxicity1.6490pLC50, mg/L
Tetrahymena Pyriformis Toxicity-0.3379pIGC50, ug/L

References

TitleJournalDatePubmed ID
Magnetic-assisted biotinylated single-chain variable fragment antibody-basedimmunoassay for amantadine detection in chicken.Anal Bioanal Chem2018 Jul 1430006725
Specific colorimetric ELISA method based on DNA hybridization reaction andnon-crosslinking gold nanoparticles aggregation for the detection of amantadine.Food Chem2018 Aug 1529622226
Development of a competitive immunochromatographic assay for the sensitivedetection of amantadine in chicken muscle.Food Chem2017 Oct 128490139
Detection of melamine in infant formula and grain powder by surface-assistedlaser desorption/ionization mass spectrometry.Rapid Commun Mass Spectrom2012 Jun 3022592982
Sunlight exposure, antioxidants, and age-related macular degeneration.Arch Ophthalmol2008 Oct18852418

Targets

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
Molecular Weight:
53925.815 Da
Mechanism of Action:
Alpha-methyldopa is a competitive inhibitor of the enzyme aromatic L-amino acid decarboxylase, which converts L-DOPA into dopamine. Dopamine is a precursor for norepinephrine (noradrenaline) and subsequently epinephrine (adrenaline). This inhibition results in reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system. This effect may lower blood pressure and cause central nervous system effects such as depression, anxiety, apathy, anhedonia, and parkinsonism. In addition, decreased dopamine may reduce its inhibitory effect on prolactin leading to signs and symptoms of hyperprolactinemia.
References
  1. SOURKES TL: Inhibition of dihydroxy-phenylalanine decarboxylase by derivatives of phenylalanine. Arch Biochem Biophys. 1954 Aug;51(2):444-56. [13189588 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
References
  1. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
General Function:
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function:
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name:
SLC15A1
Uniprot ID:
P46059
Molecular Weight:
78805.265 Da
References
  1. Han HK, Rhie JK, Oh DM, Saito G, Hsu CP, Stewart BH, Amidon GL: CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs. J Pharm Sci. 1999 Mar;88(3):347-50. [10052994 ]
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 oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Gene Name:
ADRA2A
Uniprot ID:
P08913
Molecular Weight:
48956.275 Da
Mechanism of Action:
Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
References
  1. Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. [17485976 ]