L-DOPA

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L-DOPA
3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
Levodopa3D.PNG
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 YesY
ATC code N04BA01
PubChem CID 6047
IUPHAR ligand 3639
DrugBank DB01235
ChemSpider 5824 YesY
UNII 46627O600J YesY
KEGG D00059 YesY
ChEBI CHEBI:15765 YesY
ChEMBL CHEMBL1009 YesY
Chemical data
Formula C9H11NO4 
Mol. mass 197.19 g/mol
 YesY (what is this?)  (verify)

L-DOPA (/ˌɛlˈdpə/ or /ˌlɛvˈdpə/) (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. 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, 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 with many molecules, the human body makes only one of these isomers (the L-DOPA form).

Therapeutic use[edit]

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[edit]

Herbal extracts containing L-DOPA are available; high yielding sources include Mucuna pruriens (velvet bean)[4] and broad beans,[5] while other sources include the genera Phanera, Pileostigma, Cassia, Canavalia, and Dalbergia.[6]

Biological role[edit]

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.[7]

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[edit]

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

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:

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

Possible overdose symptoms[edit]

Some test tube studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[9] 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.[10][11] 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.[12][13] 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.[14]

History[edit]

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,[15] 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:[16][17]

L-DOPA synthesis2.png

Marine adhesion[edit]

L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels.[18][19] 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.[20]

As a nootropic[edit]

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.[21]

See also[edit]

  • 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[edit]

  1. ^ Lasker Award 1969 Description, accessed April 1, 2013
  2. ^ 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
  3. ^ "L-dopa for RLS". Bandolier. 1 April 2007. Retrieved 2008-10-16. 
  4. ^ Pankaj Oudhia. "Kapikachu or Cowhage". Retrieved Nov 3, 2013. 
  5. ^ Kathrynne Holden. "Fava Beans, Levodopa, and Parkinson's Disease". Retrieved Sep 30, 2013. 
  6. ^ Ingle, P. K. (May–June 2003). "L-DOPA bearing plants". Natural Product Radiance 2 (3): 126–133. 
  7. ^ Hyland K, Clayton PT (December 1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology" (PDF). Clinical chemistry 38 (12): 2405–10. PMID 1281049. 
  8. ^ Merims D, Giladi N (2008). "Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease". Parkinsonism Relat Disord 14 (4): 273–280. doi:10.1016/j.parkreldis.2007.09.007. PMID 17988927. 
  9. ^ Cheng N, Maeda T, Kume T et al. (December 1996). "Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons". Brain Research 743 (1–2): 278–83. doi:10.1016/S0006-8993(96)01056-6. PMID 9017256. 
  10. ^ Sadigh-Eteghad, Saeed; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad; Reyhani, Bahram (2013). "Effects of Levodopa loaded chitosan nanoparticles on cell viability and caspase-3 expression in PC12 neural like cells". Neurosciences (Riyadh) 18 (3): 281–283. PMID 23887222. 
  11. ^ Basma AN, Morris EJ, Nicklas WJ, Geller HM (February 1995). "L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation". Journal of Neurochemistry 64 (2): 825–32. doi:10.1046/j.1471-4159.1995.64020825.x. PMID 7830076. 
  12. ^ Pardo B, Mena MA, Casarejos MJ, Paíno CL, De Yébenes JG (June 1995). "Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants". Brain Research 682 (1–2): 133–43. doi:10.1016/0006-8993(95)00341-M. PMID 7552304. 
  13. ^ Mytilineou C, Han SK, Cohen G (October 1993). "Toxic and protective effects of L-dopa on mesencephalic cell cultures". Journal of Neurochemistry 61 (4): 1470–8. doi:10.1111/j.1471-4159.1993.tb13642.x. PMID 8376999. 
  14. ^ Simuni T, Stern MB (June 1999). "Does levodopa accelerate Parkinson's disease?". Drugs & aging 14 (6): 399–408. doi:10.2165/00002512-199914060-00001. PMID 10408739. 
  15. ^ Cotzias, GC, Papavasiliou, PS, Gellene, R (1969). "L-dopa in parkinson's syndrome". The New England Journal of Medicine 281 (5): 272. doi:10.1056/NEJM196907312810518. PMID 5791298. 
  16. ^ Knowles, William S. (1983). "Asymmetric hydrogenation". Accounts of Chemical Research 16 (3): 106. doi:10.1021/ar00087a006. 
  17. ^ "Synthetic scheme for total synthesis of DOPA, L- (Monsanto)". UW Madison, Department of Chemistry. Retrieved Sep 30, 2013. 
  18. ^ Waite, J. Herbert et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion 81 (3–4): 1–21. doi:10.1080/00218460590944602. 
  19. ^ "Study Reveals Details Of Mussels' Tenacious Bonds". Science Daily. Aug 16, 2006. Retrieved Sep 30, 2013. 
  20. ^ Mussel Adhesive Protein Mimetics
  21. ^ Knecht, S; Breitenstein, C; Bushuven, S; Wailke, S; Kamping, S; Flöel, A; Zwitserlood, P; Ringelstein, EB (July 2004). "Levodopa: faster and better word learning in normal humans". Annals of Neurology 56 (1): 20–6. doi:10.1002/ana.20125. PMID 15236398.