L-DOPA

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l-DOPA
Skeletal formula of L-DOPA
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
intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only (some forms are OTC)
  • EU: Rx-only
renal
70–80%
Identifiers
  • (S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid
JSmol)
  • 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 checkY
  • Key:WTDRDQBEARUVNC-LURJTMIESA-N checkY
  (verify)

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal

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.[7]

Medical use

l-DOPA crosses the protective

rigidity are the most responsive symptoms while tremors are less responsive to levodopa therapy. Speech, swallowing disorders, postural instability and freezing gait are the least responsive symptoms.[9]

Once l-DOPA has entered the

form of pyridoxine. Because levodopa bypasses the enzyme tyrosine hydroxylase
, the rate-limiting step in dopamine synthesis, it is much more readily converted to dopamine than tyrosine, which is normally the natural precursor for dopamine production.

In humans, conversion of l-DOPA to dopamine does not only occur within the

DOPA decarboxylase inhibitor is not present.[3]

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.[12] It was approved by the United States Food and Drug Administration on December 21, 2018, and is marketed by Acorda Therapeutics.[13]

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.[14]

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

Biological role

Biosynthetic pathways for catecholamines and trace amines in the human brain[15][16][17]
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.[18] 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

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 AADC enzyme deficiency.[19]

l-Phenylalanine, l-tyrosine, and l-DOPA are all precursors to the biological

ascorbic acid.[20]

Marine adhesion

l-DOPA is a key

substrate.[23] The versatile chemistry of L-DOPA can be exploited in nanotechnology.[24] For example, DOPA-containing self-assembling peptides were found to form functional nanostructures, adhesives and gels.[25][26][27][28]

Side effects and adverse reactions

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

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 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

autooxidation. The increased oxidation can potentially cause mutations in DNA due to the formation of 8-oxoguanine, which is capable of pairing with adenosine during mitosis.[30]

History

In work that earned him a

Lasker Prize.[34][35] The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his 1973 book Awakenings, upon which the 1990 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.[36]

The 2001

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.[37][38][39]

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

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.[40][non-primary source needed
]

Role in plants and in the environment

In plants, L-DOPA functions as an

allelochemical which inhibits the growth of certain species, and is produced and secreted by a few legume species such as the broad bean Vicia faba and the velvet bean Mucuna pruriens.[41] Its effect is strongly dependent on the pH and the reactivity of iron in the soil.[42]

See also

References

  1. S2CID 96802274
    .
  2. ^ a b "Levodopa Use During Pregnancy". Drugs.com. 12 July 2019. Retrieved 27 September 2020.
  3. ^
    PMID 35939305
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  4. PMID 18828673
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  5. PMID 24117106
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  6. PMID 26683006
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  7. S2CID 97903386
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  8. S2CID 22874032
    .
  9. PMID 28904446
    .
  10. ^ "Medicare D". Medicare. 2014. Retrieved 12 November 2015.
  11. ^ "Lodosyn", Drugs, nd, retrieved 12 November 2012
  12. ^ "Inbrija Prescribing Information" (PDF). Retrieved February 14, 2019.
  13. ^ "Acorda Therapeutics Announces FDA Approval of INBRIJA™ (levodopa inhalation powder)". ir.acorda.com. Retrieved 2019-02-14.
  14. PMID 21328278
    .
  15. PMID 19948186
    .
  16. PMID 15860375
    .
  17. PMID 24374199
    .
  18. S2CID 2288729
    .
  19. PMID 1281049. Archived from the original
    (PDF) on 2011-06-07. Retrieved 2008-10-16.
  20. PMID 6433900
    .
  21. S2CID 136967853
    .
  22. ^ "Study Reveals Details Of Mussels' Tenacious Bonds". Science Daily. Aug 16, 2006. Retrieved Sep 30, 2013.
  23. ^ "Mussel Adhesive Protein Mimetics". Archived from the original on 2006-05-29.
  24. S2CID 234474122
    .
  25. PMID 24936704
    .
  26. PMID 28344244
    .
  27. PMID 34423482
    .
  28. PMID 25110984
    .
  29. PMID 17988927
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  30. PMID 24653659
    .
  31. S2CID 32896604
    .
  32. PMID 13869404
    .
  33. PMID 5791298
    .
  34. ^ "Lasker Award". 1969. Archived from the original on 2016-01-05., accessed April 1, 2013
  35. ISBN 978-1-934559-87-1
    – via Google eBook.
  36. PMID 5637779
    .
  37. doi:10.1021/ar00087a006
    .
  38. ^ "Synthetic scheme for total synthesis of DOPA, L- (Monsanto)". UW Madison, Department of Chemistry. Retrieved Sep 30, 2013.
  39. doi:10.1021/ed063p222
    .
  40. PMID 26524704
    .
  41. doi:10.1080/00021369.1991.10870627
    .
  42. PMID 37620733
    .

External links

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