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 OTC
Routes oral
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
DrugBank APRD00309
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
SMILES eMolecules & PubChem
 N(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.

Contents

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".[1]

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). [2]

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.[3]

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:

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.[4]

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.[5] 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.[6] 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.[7][8] 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.[9]

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,[10] 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:

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. 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

  1. ^ "L-dopa for RLS". Bandolier. 1 April 2007. http://www.medicine.ox.ac.uk/bandolier/booth/RLS/dopa.html. Retrieved 2008-10-16. 
  2. ^ http://students.cis.uab.edu/porce/page4.html
  3. ^ Hyland K, Clayton PT (December 1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology" (PDF). Clinical chemistry 38 (12): 2405–10. PMID 1281049. http://www.clinchem.org/cgi/reprint/38/12/2405.pdf. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  • Waite, J. Herbert, et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion 81: 1–21. doi:10.1080/00218460590944602. 
  • 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. 

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Look at other dictionaries:

  • dopa — [ dɔpa ] n. f. • 1949; abrév. de Dihydroxyphénylalanine ♦ Biochim. Acide aminé converti dans le sang en dopamine et dont l isomère lévogyre est utilisé dans le traitement du parkinson. ● dopa nom féminin (abréviation de DihydrOxyPhénylAlanine)… …   Encyclopédie Universelle

  • Dopa — or DOPA can refer to: L DOPA (levodopa), used in the treatment of Parkinson s disease D DOPA, a chemical compound related to L DOPA Dopa, an angel in Enochian Deleting Online Predators Act of 2006 This disambiguation page lists articles… …   Wikipedia

  • Dopa — [Kurzw. für 3 (3,4 Dihydroxyphenyl)alanin], das; : natürliche Aminosäure, die in der Adrenalin Biogenese u. im Prozess der Hautbräunung (Pigmentierung) involviert ist. Optisch aktives L( ) D. (Freiname: Levodopa) wird als Antiparkinsonmittel… …   Universal-Lexikon

  • dopa — f. bioquím. Siglas de la dihidroxifenilalanina. Molécula derivada de la tirosina que actúa como precursor de la dopamina en el la cadena metabólica de síntesis de la noradrenalina y adrenalina. La DOPA tiene aplicación médica en el tratamiento de …   Diccionario médico

  • dopa-réaction — ● dopa réaction, dopa réactions nom féminin Réaction spéciale de certaines cellules de la peau, qui deviennent noires lorsqu elles sont mises au contact d une solution de dopa. (Elle permet de mettre en évidence les cellules mélaniques non… …   Encyclopédie Universelle

  • dopa-réactions — ● dopa réaction, dopa réactions nom féminin Réaction spéciale de certaines cellules de la peau, qui deviennent noires lorsqu elles sont mises au contact d une solution de dopa. (Elle permet de mettre en évidence les cellules mélaniques non… …   Encyclopédie Universelle

  • dopa — DOPÁ, dopez, vb. I. tranz. şi refl. A( şi) administra (în mod nepermis) substanţe chimice stimulatoare spre a obţine temporar mărirea randamentului fiziologic dincolo de limitele normale, într o întrecere sportivă. – Din fr. doper. Trimis de… …   Dicționar Român

  • DOPA — Saltar a navegación, búsqueda La dihidroxifenilalanina es un sustrato prácticamente inicial de la ruta metabólica de las catecolaminas: dopamina, noradrenalina y adrenalina. Su situación es básica en la actividad metabólica de la neurona, ya que… …   Wikipedia Español

  • DOPA — dopa. (Acrón. del ingl. dihidroxiPhenyl alanine). f. Bioquím. Aminoácido derivado de la tirosina y precursor de la melanina, utilizado en el tratamiento de la enfermedad de Parkinson. * * * ● (Dihidroxifenilalanina) Sustrato prácticamente inicial …   Enciclopedia Universal

  • DOPA — statusas T sritis chemija formulė (HO)₂C₆H₃CH₂CH(NH₂)COOH atitikmenys: angl. DOPA rus. ДОПА; ДОФА ryšiai: sinonimas – 2 amino 3 (3,4 dihidroksifenil)propano rūgštis …   Chemijos terminų aiškinamasis žodynas

  • dopa — [dō′pə] n. [d(ihydr)o(xy)p(henyl)a(lanine)] an amino acid, C9H11NO4, that is converted by an enzyme in the bloodstream into dopamine: its levorotatory isomer ( L dopa) is used as a drug in treating Parkinson s disease …   English World dictionary


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