Tmic
You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Toxin, Toxin Target Database.
Record Information
Version2.0
Creation Date2009-08-06 22:55:28 UTC
Update Date2014-12-24 20:26:10 UTC
Accession NumberT3D3577
Identification
Common NameMethyldopa
ClassSmall Molecule
DescriptionMethyldopa 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 L-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).
Compound Type
  • Adrenergic alpha-2 Receptor Agonist
  • Amine
  • Antihypertensive Agent
  • Drug
  • Food Toxin
  • Metabolite
  • Organic Compound
  • Sympatholytic
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(S)-(-)-alpha-Methyldopa
3-Hydroxy-alpha-methyl-L-tyrosine
Aldomet
Aldometil
Aldomin
Alpha medopa
alpha-Methyl dopa
alpha-methyl-L-dopa
Alphamethyldopa
AMD
Dopamet
Hypolag
L-alpha-Methyldopa
L-Methyl Dopa
Medomet
Medopren
Novomedopa
Nu-Medopa
Chemical FormulaC10H13NO4
Average Molecular Mass211.215 g/mol
Monoisotopic Mass211.084 g/mol
CAS Registry Number555-30-6
IUPAC Name(2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
Traditional Namemethyldopa
SMILESC[C@](N)(CC1=CC(O)=C(O)C=C1)C(O)=O
InChI IdentifierInChI=1/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-/s2
InChI KeyInChIKey=CJCSPKMFHVPWAR-UEQNJFAPNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylpropanoic acids. Phenylpropanoic acids are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassPhenylpropanoic acids
Sub ClassNot Available
Direct ParentPhenylpropanoic acids
Alternative Parents
Substituents
  • 3-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
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite to yellowish white, odorless fine powder. Also appear as a colorless or almost colorless crystal (RxList A308, L1179).
Experimental Properties
PropertyValue
Melting Point300°C
Boiling PointNot Available
Solubility10mg/mL at 25°C
LogP-1.79
Predicted Properties
PropertyValueSource
Water Solubility2.26 g/LALOGPS
logP-2ALOGPS
logP-1.4ChemAxon
logS-2ALOGPS
pKa (Strongest Acidic)1.73ChemAxon
pKa (Strongest Basic)9.85ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area103.78 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity53.79 m³·mol⁻¹ChemAxon
Polarizability20.73 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-001i-0690000000-f54d986a8144f4a79b82View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-001i-0690000000-f54d986a8144f4a79b82View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00xu-4900000000-739bef9b92ae61fa3997View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-03l3-6719300000-8507376d6ae27047f468View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0g5i-2900000000-2d1c0ec9ad93e208b620View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0g5i-2900000000-2d1c0ec9ad93e208b620View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-014i-0910000000-3bfdb36173438fdd8a17View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-0900000000-9b6b615025e3da8f5450View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0600-4900000000-34dc05f00879ecc053bfView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-014i-0910000000-3bfdb36173438fdd8a17View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-0900000000-9b6b615025e3da8f5450View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0600-4900000000-34dc05f00879ecc053bfView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-4290000000-cdd2c737cabf0ee44d1fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000i-9410000000-d1fa6c265dd8ca539a0eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-007d-6900000000-56bdd61262b97efe050bView in MoNA
Toxicity Profile
Route of ExposureOral (1). Absorption from the gastrointestinal tract is variable but averages approximately 50%.
Mechanism of ToxicityAlthough the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa) - the precursor of norepinephrine - and of 5-hydroxytryptophan (5-HTP) - the precursor of serotonin - in the CNS and in most peripheral tissues.
MetabolismHepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates. Route of Elimination: Methyldopa is extensively metabolized. The known urinary metabolites are: alpha-methyldopa mono-O-sulfate; 3-0-methyl-alpha-methyldopa; 3,4-dihydroxyphenylacetone; alpha-methyldopamine; 3-0-methyl-alpha-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk. Half Life: The plasma half-life of methyldopa is 105 minutes.
Toxicity ValuesLD50: >1.5 g/kg (Oral, Mouse) (1) LD50: >1.5 g/kg (Oral, Rat) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use in the treatment of hypertension (1).
Minimum Risk LevelNot Available
Health EffectsAcute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction. Haemolytic anaemia, bone marrow suppression, and parkinsonism may also occur (RxList A308, L1178).
SymptomsExcessive sedation, weakness, bradycardia, dizziness, lightheadedness, bloating, constipation, distention, flatus, diarrhea, nausea, vomiting and severely low blood pressure (RxList A308).
TreatmentIn the event of overdosage, symptomatic and supportive measures should be employed. When ingestion is recent, gastric lavage or emesis may reduce absorption. When ingestion has been earlier, infusions may be helpful to promote urinary excretion. Otherwise, management includes special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity (1).
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00968
HMDB IDHMDB11754
PubChem Compound ID38853
ChEMBL IDCHEMBL459
ChemSpider ID35562
KEGG IDC07194
UniProt IDNot Available
OMIM ID
ChEBI ID61058
BioCyc IDALPHA-METHYLDOPA
CTD IDNot Available
Stitch IDAlpha-methyldopa
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkMethyldopa
References
Synthesis Reference

DrugSyn.org

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Mah GT, Tejani AM, Musini VM: Methyldopa for primary hypertension. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003893. doi: 10.1002/14651858.CD003893.pub3. [19821316 ]
  3. McCoy S, Baldwin K: Pharmacotherapeutic options for the treatment of preeclampsia. Am J Health Syst Pharm. 2009 Feb 15;66(4):337-44. doi: 10.2146/ajhp080104. [19202042 ]
  4. Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. [17485976 ]
  5. van Zwieten PA: Development and trends in the drug treatment of essential hypertension. J Hypertens Suppl. 1992 Dec;10(7):S1-12. [1363322 ]
  6. Rosenthal T, Oparil S: The effect of antihypertensive drugs on the fetus. J Hum Hypertens. 2002 May;16(5):293-8. [12082488 ]
  7. van Zwieten PA, Timmermans PB: Pharmacology and characterization of central alpha-adrenoceptors involved in the effect of centrally acting antihypertensive drugs. Chest. 1983 Feb;83(2 Suppl):340-3. [6295709 ]
  8. van Zwieten PA: Pharmacology of centrally acting hypotensive drugs. Br J Clin Pharmacol. 1980;10 Suppl 1:13S-20S. [6104975 ]
  9. Iyer KS, Thampuran RV: Beta blockade and anticonvulsant activity of propranolol. Indian J Physiol Pharmacol. 1978 Jul-Sep;22(3):293-6. [721251 ]
  10. Wikipedia. Methyldopa. Last Updated 3 August 2009. [Link]
  11. International Programme on Chemical Safety (IPCS) INCHEM (1992). Poison Information Monograph for Methyldopa. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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
References
  1. Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. [17485976 ]
  2. Kawasaki H: [Centrally acting sympathetic inhibitors for therapy of patients with hypertension] Nippon Rinsho. 1997 Aug;55(8):2081-5. [9284427 ]
  3. Head GA: Central imidazoline- and alpha 2-receptors involved in the cardiovascular actions of centrally acting antihypertensive agents. Ann N Y Acad Sci. 1999 Jun 21;881:279-86. [10415926 ]
  4. van Zwieten PA: New central mediators as targets of centrally acting antihypertensive drugs. Clin Exp Hypertens. 1996 Apr-May;18(3-4):291-303. [8743022 ]
  5. van Zwieten PA: Development and trends in the drug treatment of essential hypertension. J Hypertens Suppl. 1992 Dec;10(7):S1-12. [1363322 ]
  6. Velliquette RA, Ernsberger P: Contrasting metabolic effects of antihypertensive agents. J Pharmacol Exp Ther. 2003 Dec;307(3):1104-11. Epub 2003 Oct 13. [14557373 ]
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
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5050 uMNot AvailableBindingDB 48449
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50151600 uMNot AvailableBindingDB 48449
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 ]