L-DOPA

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L-DOPA
3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
Levodopa 3D ball.png
Systematic (IUPAC) name
(S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid
Clinical data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only Oral tablets, OTC Mucuna pruriens extract
Routes of
administration		 oral, intravenous
Pharmacokinetic data
Bioavailability 30%
Metabolism Aromatic-L-amino-acid decarboxylase
Biological half-life 0.75–1.5 hours
Excretion renal 70–80%
Identifiers
CAS Number 59-92-7 YesY
ATC code N04BA01 (WHO)
PubChem CID: 6047
IUPHAR/BPS 3639
DrugBank DB01235 YesY
ChemSpider 5824 YesY
UNII 46627O600J YesY
KEGG D00059 YesY
ChEBI CHEBI:15765 YesY
ChEMBL CHEMBL1009 YesY
Chemical data
Formula C9H11NO4
Molecular mass 197.19 g/mol
  • O=C(O)[C@@H](N)Cc1cc(O)c(O)cc1
  • 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 YesY
  • Key:WTDRDQBEARUVNC-LURJTMIESA-N YesY
  (verify)

L-DOPA (/ˌɛlˈdoʊpə/ or /ˌlɛvoʊˈdoʊpə/) (alt., 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. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS.[1][2] L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, and Prolopa. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

L-DOPA has a counterpart with opposite chirality, D-DOPA. As is true for many molecules, the human body produces only one of these isomers (the L-DOPA form).

Medical 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.[3][4] 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. 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. Excessive peripheral dopamine signaling causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with L-DOPA, are branded as Lodosyn[5] (Aton Pharma)[6] Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), and Stalevo (Orion Corporation) or with a benserazide (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Coadministration 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".[7]

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

  • The short-duration response is related to the half-life of the drug.
  • The longer-duration response depends on the accumulation of effects over at least two weeks, during which ΔFosB accumulates in nigrostriatal neurons. In the treatment of Parkinson's disease, 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; high-yielding sources include Mucuna pruriens (velvet bean),[8] and Vicia faba (broad bean),[9] while other sources include the genera Phanera, Pileostigma, Cassia, Canavalia, and Dalbergia.[10]

Biological role

Human biosynthesis pathway for trace amines and catecholamines[11][12]
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase. 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 to 3-O-methyldopa, and then further to vanillactic acid. This metabolic pathway is nonexistent 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 enzyme deficiency.[13]

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:

Although many adverse effects are 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's disease, which include:

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

Possible overdose symptoms

Some in vitro studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[15] 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.[16][17] 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.[18][19] 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.[20]

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 drug-induced (reserpine) Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960/61 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson’s disease,[21] published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered L-DOPA in patients.[22] This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,[23] who used greatly increased oral doses. 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:[24][25]

L-DOPA synthesis2.png

Marine adhesion

L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels.[26][27] 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.[28]

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 heavier people.[29]

As a treatment for age-related macular degeneration

In 2015 a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking vs. not taking L-DOPA found that the drug delayed onset of AMD by ~8 years. The authors state that significant effects were obtained for both dry and wet AMD.[30]

See also

References

  1. ↑ Citation: Lopez VM, Decatur CL, Stamer WD, Lynch RM, McKay BS (2008) L-DOPA is an endogenous ligand for OA1. PLoS Biol 6(9): e236. doi:10.1371/journal.pbio.0060236
  2. ↑ Hiroshima Y1, Miyamoto H, Nakamura F, et al. Br J Pharmacol. 2014 Jan;171(2):403-14. doi: 10.1111/bph.12459. http://www.ncbi.nlm.nih.gov/pubmed/24117106.
  3. ↑ Lasker Award 1969 Description, accessed April 1, 2013
  4. ↑ Tanya Simuni and Howard Hurtig. "Levadopa: A Pharmacologic Miracle Four Decades Later", in Parkinson's Disease: Diagnosis and Clinical Management (Google eBook). Eds. Stewart A Factor and William J Weiner. Demos Medical Publishing, 2008
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  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Mussel Adhesive Protein Mimetics
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links


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