L-DOPA

L-DOPA

Systematic (IUPAC) name
(S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid
Clinical data
Pregnancy cat.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) Mucuna pruriens extract (OTC); Oral tablets (Prescription Only) (US)
Routes	oral, intravenous
Pharmacokinetic data
Bioavailability	30%
Metabolism	Aromatic-L-amino-acid decarboxylase
Half-life	0.75–1.5 hours
Excretion	renal 70–80%
Identifiers
CAS number	59-92-7 Y
ATC code	N04BA01
PubChem	CID 6047
IUPHAR ligand	3639
DrugBank	DB01235
ChemSpider	5824 Y
UNII	46627O600J Y
KEGG	D00059 Y
ChEBI	CHEBI:15765 Y
ChEMBL	CHEMBL1009 Y
Chemical data
Formula	C9H11NO4
Mol. mass	197.19 g/mol
SMILES O=C(O)[C@@H](N)Cc1cc(O)c(O)cc1
InChI InChI=1S/C9H11NO4/c10-6(9(13)14)3-5-1-2-7(11)8(12)4-5/h1-2,4,6,11-12H,3,10H2,(H,13,14)/t6-/m0/s1 Y Key:WTDRDQBEARUVNC-LURJTMIESA-N Y
Y (what is this?)  (verify)

L-DOPA (L-3,4-dihydroxyphenylalanine) is a chemical that is made and used as part of the normal biology of humans, some animals and plants. Some animals and humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc. As a drug it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Therapeutic use

L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. This treatment was made practical and proven clinically by George Cotzias and his coworkers, for which they won the 1969 Lasker Prize.^[1][2] Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B₆) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.

Besides the central nervous system, L-DOPA is also converted into dopamine from within the peripheral nervous system. The resulting hyperdopaminergia causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to co-administer (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines combining L-DOPA and carbidopa are branded as Lodosyn, Sinemet, Parcopa, Atamet, Stalevo) or with a benserazide (combination medicines are branded Madopar, Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Co-administration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration, a phenomenon that historically caused great confusion.

In addition, L-DOPA, co-administered with a peripheral DDCI, has been investigated as a potential treatment for restless leg syndrome. However, studies have demonstrated "no clear picture of reduced symptoms".^[3]

The two types of response seen with administration of L-DOPA are:

• Short-duration response, which is related to the half-life of the drug
• Longer-duration response, which depends on the accumulation of effects over at least two weeks. This response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.

Dietary supplements

Herbal extracts containing L-DOPA are available; sources include Mucuna pruriens (velvet bean)^[4] and broad beans.^[5]

Biological role

Biosynthesis of dopamine

L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH). It is also the precursor for the monoamine or catecholamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of L-DOPA.

L-DOPA can be directly metabolized by catechol-O-methyl transferase (COMT) to 3-O-methyldopa (3-OMD), and then further to vanillactic acid (VLA). This metabolic pathway is non-existent in the healthy body, but becomes important after peripheral L-DOPA administration in patients with Parkinson's Disease or in the rare cases of patients with aromatic L-amino acid decarboxylase (AADC) enzyme deficiency.^[6]

The prefix L- refers to its property of levorotation (compared with dextrorotation or D-DOPA).

L-Phenylalanine, L-tyrosine, and L-DOPA, are all precursors to the biological pigment melanin. The enzyme tyrosinase catalyzes the oxidation of L-DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin oligomers.

Side effects

The side effects of L-DOPA may include, but not limited to:

• Hypotension, especially if the dosage is too high
• Arrhythmias, although these are uncommon
• Nausea, which is often reduced by taking the drug with food, although protein interferes with drug absorption
• Gastrointestinal bleeding
• Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
• Hair loss
• Disorientation and confusion
• Extreme emotional states, particularly anxiety, but also excessive libido
• Vivid dreams or insomnia
• Auditory or visual hallucinations
• Effects on learning; there is some evidence that it improves working memory, while impairing other complex functions
• Somnolence and narcolepsy
• A condition similar to stimulant psychosis

Although there are many adverse effects associated with L-DOPA, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.

More serious are the effects of chronic L-DOPA administration in the treatment of Parkinson disease, which include:

• End-of-dose deterioration of function
• On/off oscillations
• Freezing during movement
• Dose failure (drug resistance)
• Dyskinesia at peak dose (levodopa-induced dyskinesia)
• Possible serotonin depletion: Recent studies have demonstrated that use of L-DOPA without simultaneously giving proper levels of serotonin precursors depletes serotonin^{[citation needed]}
• Possible dopamine dysregulation: The long-term use of L-DOPA in Parkinson's Disease has been linked to the so-called dopamine dysregulation syndrome.^[7]

Clinicians will try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.

Possible overdose symptoms

Some test tube studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.^[8] Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with L-DOPA.^[9] Other authors have attributed the observed toxic effects of L-DOPA in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.^[10][11] There is no evidence of neurotoxicity in patients with Parkinson's Disease and it is generally considered safe, but some controversy surrounds its use in the treatment of Parkinson's Disease, given some test tube data indicate a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.^[12]

History

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering L-DOPA to animals with Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,^[13] who greatly increased the dose. The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his book Awakenings, upon which the movie of the same name is based.

The 2001 Nobel Prize in Chemistry was also related to L-DOPA: the Nobel Committee awarded one quarter of the prize to William S. Knowles for his work on chirally catalysed hydrogenation reactions, the most noted example of which was used for the synthesis of L-DOPA:^[14][15]

Marine adhesion

L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels.^[16][17] It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. L-DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible substrate.^[18]

As a nootropic

One double-blind, placebo controlled study (n=40) found that L-DOPA enhances learning of pseudowords. The drug group showed better learning in all comparisons. Furthermore, a dose-response relationship was tested and found to be the case: lighter people from the drug group did better than the non-light people.^[19]

See also

• D-DOPA (Dextrodopa)
• L-DOPS (Droxidopa)
• Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
• Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
• Norepinephrine (Noradrenaline; Levophed, etc.)
• Epinephrine (Adrenaline; Adrenalin, EpiPen, Twinject, etc.)

References

v t e The 20 common amino acids General topics Protein Peptide Genetic code By properties Aliphatic Branched-chain amino acids (Valine Isoleucine Leucine) Methionine Alanine Proline Glycine Aromatic Phenylalanine Tyrosine Tryptophan Histidine Polar, uncharged Asparagine Glutamine Serine Threonine Positive charge (pKa) Lysine (≈10.8) Arginine (≈12.5) Histidine (≈6.1) Negative charge (pKa) Aspartic acid (≈3.9) Glutamic acid (≈4.1) Cysteine (≈8.3) Tyrosine (≈10.1) Other classifications Essential amino acid Ketogenic amino acid Glucogenic amino acid Non-proteinogenic amino acid Biochemical families: carbohydrates alcohols glycoproteins glycosides lipids eicosanoids fatty acids / intermediates phospholipids sphingolipids steroids nucleic acids constituents / intermediates proteins Amino acids / intermediates tetrapyrroles / intermediates