Levodopa

Structural formula
General
Non-proprietary name	Levodopa
other names	L -DOPA; L -3,4-dihydroxyphenylalanine; ( S ) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid; ( S ) -2-amino-3- (3,4-dihydroxyphenyl) propionic acid;
Molecular formula	C 9 H 11 NO 4
Brief description	white solid; white or almost white crystalline powder;
External identifiers / databases
EC number	200-445-2
ECHA InfoCard	100,000,405
PubChem	6047
ChemSpider	5824
DrugBank	DB01235
Wikidata	Q300989
Drug information
ATC code	N04 BA01
Drug class	Parkinson's medication
Mechanism of action	Dopamine precursor
properties
Molar mass	197.19 g · mol -1
Physical state	firmly
Melting point	276-278 ° C or 284-285 ° C
solubility	soluble in water; Slightly soluble in water, practically insoluble in ethanol 96%, easily soluble in 1 M hydrochloric acid , slightly soluble in 0.1 M hydrochloric acid;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 302-315-319-335
	P: 261-305 + 351 + 338
Toxicological data	1780 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Levodopa , and L -DOPA , is the abbreviation for L -3,4- D ihydr o xy p henyl a lanin, a non-proteinogenic α-amino acid , which in the body from tyrosine by the enzyme tyrosine hydroxylase is formed.

Biological importance

L- DOPA is a preliminary stage in the biosynthesis of the messenger substances ( neurotransmitters ) adrenaline , noradrenaline , betalaine and dopamine as well as melanins and isoquinoline alkaloids .

In the case of mussels , L- DOPA forms the main component of the adhesive with which mussels adhere to solid surfaces. The function of L -DOPA here is that it, built into the protein chain of the adhesive, increases the hydrophilicity through its hydroxyl groups . This is important so that the adhesive released into the surrounding sea water achieves a better adhesion effect with the surface of the sub-floor.

Use as a medicinal substance

As drug is L -DOPA usually with its generic name called levodopa. In many European countries, including Germany, Austria and Switzerland, levodopa requires a prescription .

pharmacology

Since levodopa, in contrast to the aforementioned transmitters dopamine , adrenaline and noradrenaline, is able to cross the blood-brain barrier , it is suitable for the treatment of diseases that result from a deficiency in these, such as Parkinson's disease , which is deficient associated with dopamine. In order to prevent the premature breakdown of levodopa in the body periphery (outside the liquor space ) to dopamine, it is combined with either a decarboxylase inhibitor ( carbidopa , benserazide ) or a catechol-O-methyltransferase inhibitor ( entacapone , tolcapone ). After crossing the blood-brain barrier, levodopa is then metabolized into dopamine, which develops the actual desired pharmacological effectiveness. Thus, levodopa is a prodrug .

application areas

As a medicinal substance , levodopa, the effect of which was observed in 1957 by Arvid Carlsson and his research group, was marketed under the brand name Madopar in 1973 by Hoffmann-La Roche for the treatment of Parkinson's disease. The fixed combination levodopa + carbidopa was included in 1977 by the World Health Organization (WHO) in the list of indispensable drugs of the World Health Organization . Due to side effects in long-term use in Parkinson's patients, attempts are now being made, especially in younger Parkinson's patients, to delay treatment with levodopa and to treat it primarily with dopamine agonists .

Even the restless legs syndrome (RLS) is often treated with levodopa. Levodopa is also increasingly used in the treatment of Huntington 's disease. In addition, L-DOPA can be used off-label for the treatment of negative symptoms of schizophrenia simplex . A benefit in emotional withdrawal, dulled affect , tendencies towards social isolation and apathy could be shown.

Side effects

Side effects may include nausea, dizziness and circulatory problems. With high doses up to overdose, side effects such as dyskinesia or psychological symptoms such as insomnia and hallucinations can occur. If the patient is stopped suddenly, levodopa withdrawal syndrome can occur.

Chemical properties

L -DOPA is readily soluble in water (3.3 g / l at 25 ° C), poorly soluble in ethanol and insoluble in diethyl ether .

Structural descendants

The derivative ¹⁸ F-DOPA ( fluorodopa ( ¹⁸ F) ) substituted at C-2 with the fluorine isotope ¹⁸ F is used in positron emission tomography to diagnose neuroendocrine tumors .

Trivia

The film Awakenings (German time of awakening , with Robert De Niro and Robin Williams , director: Penny Marshall , 1990) based on a book by Oliver Sacks addresses the short-term therapeutic successes of patients with European sleeping sickness with L- DOPA.

Trade names

Combination preparations

with benserazide: Levobens (A), Levodopa comp (D), Levopar (D), Madopar (D, A, CH), PK-Levo (D), Restex (D, A) and other generics
with Carbidopa: Duodopa (D, A, CH), Isicom (D), Sinemet (A, CH), Stalevo (D, A, CH), Striaton (D) and other generics
with carbidopa and entacapone : Stalevo (D, A, CH)

literature

Paul Foley: Beans, roots and leaves: A brief history of the pharmacological therapy of parkinsonism. In: Würzburg medical history reports. Volume 22, 2003, pp. 215-234, here: pp. 224-229.

Individual evidence

↑ ^a ^b ^c ^d data sheet 3,4-dihydroxy-L-phenylalanine from Sigma-Aldrich , accessed on April 7, 2011 ( PDF ).
↑ ^a ^b European Pharmacopoeia 9.0 (2017), p. 2892.
^ The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 946-947, ISBN 978-0-911910-00-1 .
↑ Data sheet 3,4-Dihydroxy-L-phenylalanine from AlfaAesar, accessed on July 31, 2010 ( PDF )(JavaScript required) .
^ JH Waite, ML Tanzer: The bioadhesive of Mytilus byssus: a protein containing L-dopa. In: Biochemical and biophysical research communications . Volume 96, Number 4, October 1980, pp. 1554-1561, PMID 7447941 .
^ Arvid Carlsson, Margit Lindqvist, Tor Magnusson: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. In: Nature. Volume 180, 1957, p. 1200.
^ Paul Foley: Beans, roots and leaves: A brief history of the pharmacological therapy of parkinsonism. In: Würzburg medical history reports. Volume 22, 2003, pp. 215-234, here: pp. 224 f.
↑ WHO Model List of Essential Medicines (PDF file; 432 kB) , accessed on September 20, 2012.
↑ H. Scholz, C. Trenkwalder et al: Levodopa for restless legs syndrome. In: Cochrane database of systematic reviews (online). Number 2, 2011, p. CD005504, doi : 10.1002 / 14651858.CD005504.pub2 . PMID 21328278 . (Review).
^ JI Hoff, BJ van Hilten, RA Roos: A review of the assessment of dyskinesias. In: Movement disorders. Volume 14, Number 5, September 1999, pp. 737-743, PMID 10495034 .
↑ Gerlach J., Lühdorf K .: The effect of L-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: a double-blind cross-over trial with Madopar and placebo . In: Psychopharmacologia . 44, No. 1, 1975, pp. 105-10. doi : 10.1007 / bf00421193 . PMID 706 .
^ Medicines Commission of the German Medical Association: Medicinal Ordinances, 22nd edition, 2009, MMI-Verlag.
↑ S. Kauhanen, M. Seppänen et al .: Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients. In: The Journal of clinical endocrinology and metabolism . Volume 92, Number 4, April 2007, pp. 1237-1244, doi : 10.1210 / jc.2006-1479 . PMID 17227804 .

[sigma-1] ta sheet 3,4-dihydroxy-L-phenylalanine from Sigma-Aldrich , accessed on April 7, 2011 ( PDF ).

[ep9.0-2] European Pharmacopoeia 9.0 (2017), p. 2892.

[MERCK_Index-3] The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 946-947, ISBN 978-0-911910-00-1 .

[Alfa-4] Data sheet 3,4-Dihydroxy-L-phenylalanine from AlfaAesar, accessed on July 31, 2010 ( PDF )(JavaScript required) .

[PMID7447941-5] JH Waite, ML Tanzer: The bioadhesive of Mytilus byssus: a protein containing L-dopa. In: Biochemical and biophysical research communications . Volume 96, Number 4, October 1980, pp. 1554-1561, PMID 7447941 .

[6] Arvid Carlsson, Margit Lindqvist, Tor Magnusson: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. In: Nature. Volume 180, 1957, p. 1200.

[7] Paul Foley: Beans, roots and leaves: A brief history of the pharmacological therapy of parkinsonism. In: Würzburg medical history reports. Volume 22, 2003, pp. 215-234, here: pp. 224 f.

[8] WHO Model List of Essential Medicines (PDF file; 432 kB) , accessed on September 20, 2012.

[PMID21328278-9] H. Scholz, C. Trenkwalder et al: Levodopa for restless legs syndrome. In: Cochrane database of systematic reviews (online). Number 2, 2011, p. CD005504, doi : 10.1002 / 14651858.CD005504.pub2 . PMID 21328278 . (Review).

[PMID10495034-10] JI Hoff, BJ van Hilten, RA Roos: A review of the assessment of dyskinesias. In: Movement disorders. Volume 14, Number 5, September 1999, pp. 737-743, PMID 10495034 .

[SchiophreniaSimplex-11] Gerlach J., Lühdorf K .: The effect of L-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: a double-blind cross-over trial with Madopar and placebo . In: Psychopharmacologia . 44, No. 1, 1975, pp. 105-10. doi : 10.1007 / bf00421193 . PMID 706 .

[12] Medicines Commission of the German Medical Association: Medicinal Ordinances, 22nd edition, 2009, MMI-Verlag.

[PMID17227804-13] S. Kauhanen, M. Seppänen et al .: Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients. In: The Journal of clinical endocrinology and metabolism . Volume 92, Number 4, April 2007, pp. 1237-1244, doi : 10.1210 / jc.2006-1479 . PMID 17227804 .