L-DOPA

L-DOPA

Clinical data
Pregnancy category	AU: B3
Routes of administration	oral
ATC code	N04BA01 (WHO)
Legal status
Legal status	In general: Over-the-counter (OTC)
Pharmacokinetic data
Bioavailability	30%
Metabolism	Aromatic-L-amino-acid decarboxylase
Elimination half-life	0.75–1.5 hours
Excretion	renal 70–80%
Identifiers
IUPAC name (S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid
CAS Number	59-92-7 Y
PubChem CID	6047
DrugBank	APRD00309 Y
ChemSpider	5824 Y
UNII	46627O600J
KEGG	D00059 Y
ChEBI	CHEBI:15765 N
ChEMBL	ChEMBL1009 Y
CompTox Dashboard (EPA)	DTXSID9023209
ECHA InfoCard	100.000.405
Chemical and physical data
Formula	C9H11NO4
Molar mass	197.19 g/mol g·mol−1
3D model (JSmol)	Interactive image
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
NY (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 some animals and plants. Some animals including 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 originally developed by George Cotzias and his coworkers. 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 CNS, 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. In order 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".

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

• 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. The most common plant source of L-DOPA marketed in this manner is Mucuna pruriens (Velvet Bean).

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 PD or in the rare cases of patients with aromatic L-amino acid decarboxylase (AADC) enzyme deficiency.

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

L-Phenylalanine, L-tyrosine, and L-DOPA, are all are 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 and/or insomnia
• Auditory and/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 levodopa 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
• Possible serotonin depletion: Recent studies have demonstrated that use of L-DOPA without simultaneously giving proper levels of serotonin precursors depletes serotonin
• Possible dopamine dysregulation: The long-term use of L-DOPA in PD has been linked to the so-called dopamine dysregulation syndrome.

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

Toxicity

Some scientific studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment. 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. 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. Though L-DOPA is generally considered safe, some controversy surrounds its use in the treatment of PD, given some data indicating a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.

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 would cause a reduction in their intensity. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers, 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-fourth 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:

Marine adhesion

L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels. 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.

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

• Waite, J. Herbert; et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion. 81: 1–21. doi:10.1080/00218460590944602. {{cite journal}}: Explicit use of et al. in: |author= (help)
• Messersmith, Phillip B.; et al. (2006). "Rapid Gel Formation and Adhesion in Photocurable and Biodegradable Block Copolymers with High DOPA Content". Macromolecules. 39: 1740–1748. doi:10.1021/ma0518959. {{cite journal}}: Explicit use of et al. in: |author= (help)

External links

• Study Reveals Details Of Mussels' Tenacious Bonds