Methyldopa
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Basic Info
Common Name | Methyldopa(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 ID | F04861 |
CAS Number | 555-30-6 |
PubChem CID | 38853 |
Formula | C10H13NO4 |
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 |
Wikipedia | Methyldopa |
Synonyms | l-alpha-Methyldopa methyldopa 555-30-6 Alphamethyldopa Aldomet Alpha medopa Dopamet alpha-Methyl dopa Baypresol Hyperpax |
Classifies | Predicted: Animal Toxin |
Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
Kingdom | Organic compounds |
Superclass | Phenylpropanoids and polyketides |
Class | Phenylpropanoic acids |
Subclass | Not available |
Intermediate Tree Nodes | Not available |
Direct Parent | Phenylpropanoic acids |
Alternative Parents |
|
Molecular Framework | Aromatic homomonocyclic compounds |
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 |
Description | This 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 Name | Property Value |
---|---|
Molecular Weight | 211.217 |
Hydrogen Bond Donor Count | 4 |
Hydrogen Bond Acceptor Count | 5 |
Rotatable Bond Count | 3 |
Complexity | 246 |
Monoisotopic Mass | 211.084 |
Exact Mass | 211.084 |
XLogP | -1.9 |
Formal Charge | 0 |
Heavy Atom Count | 15 |
Defined Atom Stereocenter Count | 1 |
Undefined Atom Stereocenter Count | 0 |
Defined Bond Stereocenter Count | 0 |
Undefined Bond Stereocenter Count | 0 |
Isotope Atom Count | 0 |
Covalently-Bonded Unit Count | 1 |
ADMET
Model | Result | Probability |
---|---|---|
Absorption | ||
Blood-Brain Barrier | BBB- | 0.9276 |
Human Intestinal Absorption | HIA+ | 0.9374 |
Caco-2 Permeability | Caco2- | 0.8957 |
P-glycoprotein Substrate | Substrate | 0.6066 |
P-glycoprotein Inhibitor | Non-inhibitor | 0.9852 |
Non-inhibitor | 0.9895 | |
Renal Organic Cation Transporter | Non-inhibitor | 0.9357 |
Distribution | ||
Subcellular localization | Mitochondria | 0.4823 |
Metabolism | ||
CYP450 2C9 Substrate | Non-substrate | 0.7757 |
CYP450 2D6 Substrate | Non-substrate | 0.8000 |
CYP450 3A4 Substrate | Non-substrate | 0.6053 |
CYP450 1A2 Inhibitor | Non-inhibitor | 0.9045 |
CYP450 2C9 Inhibitor | Non-inhibitor | 0.9369 |
CYP450 2D6 Inhibitor | Non-inhibitor | 0.9491 |
CYP450 2C19 Inhibitor | Non-inhibitor | 0.9233 |
CYP450 3A4 Inhibitor | Non-inhibitor | 0.8640 |
CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.9551 |
Excretion | ||
Toxicity | ||
Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9939 |
Non-inhibitor | 0.9629 | |
AMES Toxicity | Non AMES toxic | 0.8185 |
Carcinogens | Non-carcinogens | 0.8997 |
Fish Toxicity | High FHMT | 0.8770 |
Tetrahymena Pyriformis Toxicity | High TPT | 0.7375 |
Honey Bee Toxicity | Low HBT | 0.6296 |
Biodegradation | Not ready biodegradable | 0.8077 |
Acute Oral Toxicity | IV | 0.6203 |
Carcinogenicity (Three-class) | Non-required | 0.7090 |
Model | Value | Unit |
---|---|---|
Absorption | ||
Aqueous solubility | -1.8784 | LogS |
Caco-2 Permeability | -0.3080 | LogPapp, cm/s |
Distribution | ||
Metabolism | ||
Excretion | ||
Toxicity | ||
Rat Acute Toxicity | 1.6281 | LD50, mol/kg |
Fish Toxicity | 1.6490 | pLC50, mg/L |
Tetrahymena Pyriformis Toxicity | -0.3379 | pIGC50, ug/L |
References
Title | Journal | Date | Pubmed ID |
---|---|---|---|
Magnetic-assisted biotinylated single-chain variable fragment antibody-basedimmunoassay for amantadine detection in chicken. | Anal Bioanal Chem | 2018 Jul 14 | 30006725 |
Specific colorimetric ELISA method based on DNA hybridization reaction andnon-crosslinking gold nanoparticles aggregation for the detection of amantadine. | Food Chem | 2018 Aug 15 | 29622226 |
Development of a competitive immunochromatographic assay for the sensitivedetection of amantadine in chicken muscle. | Food Chem | 2017 Oct 1 | 28490139 |
Detection of melamine in infant formula and grain powder by surface-assistedlaser desorption/ionization mass spectrometry. | Rapid Commun Mass Spectrom | 2012 Jun 30 | 22592982 |
Sunlight exposure, antioxidants, and age-related macular degeneration. | Arch Ophthalmol | 2008 Oct | 18852418 |
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
- 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
- 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
- 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
- Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. [17485976 ]