L-DOPA

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l-DOPA
3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
Skeletal formula of L-DOPA
L-DOPA-from-xtal-view-2-3D-bs-17.png
Ball-and-stick model of the zwitterionic form of L-DOPA found in the crystal structure[1]
Clinical data
Pronunciation/ˌɛlˈdoʊpə/, /ˌlɛvoʊˈdoʊpə/
Trade namesLarodopa, Dopar, Inbrija, others
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa619018
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only (some forms are OTC)
  • EU: Rx-only
Pharmacokinetic data
Bioavailability30%
MetabolismAromatic-l-amino-acid decarboxylase
Elimination half-life0.75–1.5 hours
Excretionrenal 70–80%
Identifiers
IUPAC name
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.405 Edit this at Wikidata
Chemical and physical data
FormulaC9H11NO4
Molar mass197.190 g·mol−1
3D model (JSmol)
SMILES
InChI
  

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of humans, as well as some animals and plants. Humans, as well as a portion of the other animals that utilize l-DOPA in their biology, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS.[3][4] 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, and Stalevo. 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). The enantiomeric purity of l-DOPA may be analyzed by determination of the optical rotation or by chiral thin-layer chromatography (chiral TLC).[5]

Medical use[]

l-DOPA crosses the protective blood-brain barrier, whereas dopamine itself cannot.[6] Thus, l-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. 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.

In humans, conversion of l-DOPA to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system perform the same task. Thus administering l-DOPA alone will lead to increased dopamine signaling in the periphery as well. Excessive peripheral dopamine signaling is undesirable as it 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[7] (Aton Pharma)[8] Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Syndopa 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).

Inbrija (previously known as CVT-301) is an inhaled powder formulation of levodopa indicated for the intermittent treatment of off episodes in patients with Parkinson's disease currently taking carbidopa/levodopa.[9] It was approved by the United States Food and Drug Administration on December 21, 2018 and is marketed by Acorda Therapeutics.[10]

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, is efficacious for the short term treatment of restless leg syndrome.[11]

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.

Biological role[]

Biosynthetic pathways for catecholamines and trace amines in the human brain[12][13][14]
Graphic of catecholamine and trace amine biosynthesis
L-Phenylalanine
L-Tyrosine
L-DOPA
Epinephrine
Phenethylamine
p-Tyramine
Dopamine
Norepinephrine
N-Methylphenethylamine
N-Methyltyramine
p-Octopamine
Synephrine
3-Methoxytyramine
AADC
AADC
AADC
primary
pathway
PNMT
PNMT
PNMT
PNMT
brain
CYP2D6
minor
pathway
COMT
DBH
DBH
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

l-DOPA is produced from the amino acid l-tyrosine by the enzyme tyrosine hydroxylase. l-DOPA can act as an l-tyrosine mimetic and be incorporated into proteins by mammalian cells in place of L-tyrosine, generating protease-resistant and aggregate-prone proteins in vitro and may contribute to neurotoxicity with chronic l-DOPA administration.[15] 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 by aromatic l-amino acid decarboxylase (AADC).

l-DOPA can be directly metabolized by catechol-O-methyl transferase to 3-O-methyldopa, and then further to . 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 AADC enzyme deficiency.[16]

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. In addition, tyrosinase can convert tyrosine directly to l-DOPA in the presence of a reducing agent such as ascorbic acid.[17]

Side effects and adverse reactions[]

The side effects of l-DOPA may include:

  • Hypertension, 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 reduces drug absorption. l-DOPA is an amino acid, so protein competitively inhibits l-DOPA 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; some evidence indicates it improves working memory, while impairing other complex functions
  • Somnolence and narcolepsy
  • A condition similar to stimulant psychosis

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:

  • End-of-dose deterioration of function
  • On/off oscillations
  • Freezing during movement
  • Dose failure (drug resistance)
  • Dyskinesia at peak dose (levodopa-induced dyskinesia)
  • Possible dopamine dysregulation: The long-term use of l-DOPA in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.[18]

Clinicians try to avoid these side effects and adverse reactions by limiting l-DOPA doses as much as possible until absolutely necessary.

The long term use of L-Dopa increases oxidative stress through monoamine oxidase led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of reactive oxygen species (H2O2) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe2+ ions in striatum via the Fenton reaction and the intracellular auto-oxidation. The increased oxidation can potentially cause mutations in the DNA due to the formation of 8-oxoguanine which is capable of pairing with adenosine.[19]

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,[20] published together with the neurologist dramatic therapeutic antiparkinson effects of intravenously administered l-DOPA in patients.[21] This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,[22] for which they won the 1969 Lasker Prize.,[23][24] 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 first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.[25]

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.[26][27][28]

Synthesis of l-DOPA via hydrogenation with C2-symmetric diphosphine.

Dietary supplements[]

Herbal extracts containing l-DOPA are available; high-yielding sources include Mucuna pruriens (velvet bean),[29] and Vicia faba (broad bean), while other sources include the genera Phanera, Piliostigma, Cassia, Canavalia, and Dalbergia.[30]

Marine adhesion[]

l-DOPA is a key compound in the formation of , such as those found in mussels.[31][32] 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.[33]

Research[]

Age-related macular degeneration[]

In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking l-DOPA found that the drug delayed onset of AMD by around 8 years. The authors state that significant effects were obtained for both dry and wet AMD.[34][non-primary source needed]

See also[]

  • d-DOPA (Dextrodopa)
  • l-DOPS (Droxidopa)
  • Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
  • Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
  • Ciladopa
  • Neuroleptic malignant syndrome
  • Melanin (a metabolite)

References[]

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  4. ^ Hiroshima Y, Miyamoto H, Nakamura F, Masukawa D, Yamamoto T, Muraoka H, Kamiya M, Yamashita N, Suzuki T, Matsuzaki S, Endo I, Goshima Y (January 2014). "The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii". British Journal of Pharmacology. 171 (2): 403–14. doi:10.1111/bph.12459. PMC 3904260. PMID 24117106.
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  23. ^ Lasker Award 1969 Description, accessed April 1, 2013
  24. ^ 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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  29. ^ Pankaj Oudhia. "Kapikachu or Cowhage". Retrieved Nov 3, 2013.
  30. ^ Ingle PK (May–June 2003). "L-DOPA bearing plants". Natural Product Radiance. 2 (3): 126–133.
  31. ^ Waite JH, Andersen NH, Jewhurst S, Sun C (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion. 81 (3–4): 1–21. doi:10.1080/00218460590944602. S2CID 136967853.
  32. ^ "Study Reveals Details Of Mussels' Tenacious Bonds". Science Daily. Aug 16, 2006. Retrieved Sep 30, 2013.
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  34. ^ Brilliant MH, Vaziri K, Connor TB, Schwartz SG, Carroll JJ, McCarty CA, Schrodi SJ, Hebbring SJ, Kishor KS, Flynn HW, Moshfeghi AA, Moshfeghi DM, Fini ME, McKay BS (March 2016). "Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration". The American Journal of Medicine. 129 (3): 292–8. doi:10.1016/j.amjmed.2015.10.015. PMC 4841631. PMID 26524704.

External links[]

  • "Levodopa". Drug Information Portal. U.S. National Library of Medicine.
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