| Candidate ID: | R0348 |
| Source ID: | DB00968 |
| Source Type: | approved |
| Compound Type: |
small molecule
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| Compound Name: |
Methyldopa
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| Synonyms: |
(S)-(-)-alpha-Methyldopa; 3-Hydroxy-alpha-methyl-L-tyrosine; Alpha medopa; alpha-Methyl dopa; alpha-methyl-L-dopa; Alphamethyldopa; AMD; Anhydrous methyldopa; L-alpha-Methyldopa; L-Methyl Dopa; Methyl dopa; Methyldopa; Methyldopa anhydrous; α-Methyl dopa; α-methyl-L-dopa
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| Molecular Formula: |
C10H13NO4
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| SMILES: |
C[C@](N)(CC1=CC=C(O)C(O)=C1)C(O)=O
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| Structure: |
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| DrugBank Description: |
Methyldopa, or α-methyldopa, is a centrally acting sympatholytic agent and an antihypertensive agent. It is an analog of DOPA (3,4‐hydroxyphenylanine), and it is a prodrug, meaning that the drug requires biotransformation to an active metabolite for therapeutic effects. Methyldopa works by binding to alpha(α)-2 adrenergic receptors as an agonist, leading to the inhibition of adrenergic neuronal outflow and reduction of vasoconstrictor adrenergic signals. Methyldopa exists in two isomers D-α-methyldopa and L-α-methyldopa, which is the active form.
First introduced in 1960 as an antihypertensive agent, methyldopa was considered to be useful in certain patient populations, such as pregnant women and patients with renal insufficiency. Since then, methyldopa was largely replaced by newer, better-tolerated antihypertensive agents; however, it is still used as monotherapy or in combination with . Methyldopa is also available as intravenous injection, which is used to manage hypertension when oral therapy is unfeasible and to treat hypertensive crisis.
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| CAS Number: |
555-30-6
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| Molecular Weight: |
211.2145
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| DrugBank Indication: |
Methyldopa is indicated for the management of hypertension as monotherapy or in combination with hydrochlorothiazide. Methyldopa injection is used to manage hypertensive crises.
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| DrugBank Pharmacology: |
Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors. Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure. Methyldopa causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine. Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension. Methyldopa also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur.
Following oral administration, blood-pressure-lowering effects are observed within 12 to 24 hours in most patients, and a maximum reduction in blood pressure occurs in 4 to 6 hours. Blood pressure returns to pre-treatment levels within 24 to 48 hours following drug discontinuation. Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 10 to 16 hours.
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| DrugBank MoA: |
The exact mechanism of methyldopa is not fully elucidated; however, the main mechanisms of methyldopa involve its actions on alpha-adrenergic receptor and the aromatic L-amino acid decarboxylase enzyme, to a lesser extent. The sympathetic outflow is regulated by alpha (α)-2 adrenergic receptors and imidazoline receptors expressed on adrenergic neurons within the rostral ventrolateral medulla. Methyldopa is metabolized to α‐methylnorepinephrine via dopamine beta-hydroxylase activity and, consequently, alpha-methylepinephrine via phenylethanolamine-N-methyltransferase activity. Mediating the therapeutic effects of methyldopa, α‐methylnorepinephrine and α-methylepinephrine active metabolites are agonists at presynaptic alpha-2 adrenergic receptors in the brainstem. Stimulating alpha-2 adrenergic receptors results in the inhibition of adrenergic neuronal outflow and attenuation of norepinephrine release in the brainstem. Consequently, the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system is reduced, leading to a reduction in blood pressure.
The L-isomer of alpha-methyldopa also reduces blood pressure by inhibiting aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase, which is an enzyme responsible for the syntheses of dopamine and serotonin. Inhibiting this enzyme leads to depletion of biogenic amines such as norepinephrine. However, inhibition of aromatic L-amino acid decarboxylase plays a minimal role in the blood-pressure‐lowering effect of methyldopa.
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| Targets: |
Alpha-2A adrenergic receptor agonist; Aromatic-L-amino-acid decarboxylase inhibitor
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| Inclusion Criteria: |
Therapeutic strategy associated
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