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-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal
biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditar ...
of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA, make it via biosynthesis from the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
-tyrosine. -DOPA is the precursor to the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
s
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
,
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
(noradrenaline), and epinephrine (adrenaline), which are collectively known as
catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol ( benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a ...
s. Furthermore, -DOPA itself mediates neurotrophic factor release by the brain and CNS. -DOPA can be manufactured and in its pure form is sold as a
psychoactive drug A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. T ...
with the
INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and dopamine-responsive dystonia. -DOPA has a counterpart with opposite chirality, -DOPA. As is true for many molecules, the human body produces only one of these
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. ...
s (the -DOPA form). The enantiomeric purity of -DOPA may be analyzed by determination of the optical rotation or by chiral thin-layer chromatography.


Medical use

-DOPA crosses the protective blood–brain barrier, whereas
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
itself cannot. Thus, -DOPA is used to increase dopamine concentrations in the treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, Parkinsonism, dopamine-responsive dystonia and
Parkinson-plus syndrome Parkinson-plus syndromes (PPS) are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease ( tremor, rigidity, akinesia/bradykinesia, and postural instability) with additional features that distinguish them f ...
. The therapeutic efficacy is different for different kinds of symptoms. Bradykinesia and 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. Once -DOPA has entered the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
, it is converted into dopamine by the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
aromatic -amino acid decarboxylase, also known as DOPA decarboxylase.
Pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'- phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-depende ...
( vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with -DOPA, usually in the
form Form is the shape, visual appearance, or configuration of an object. In a wider sense, the form is the way something happens. Form also refers to: * Form (document), a document (printed or electronic) with spaces in which to write or enter dat ...
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 -DOPA to dopamine does not only occur within the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. Cells in the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...
perform the same task. Thus administering -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 effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister (with -DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with -DOPA, are branded as Lodosyn ( Aton Pharma) 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 -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. It was approved by the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
on December 21, 2018, and is marketed by Acorda Therapeutics. Coadministration of pyridoxine without a DDCI accelerates the peripheral
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
of -DOPA to such an extent that it negates the effects of -DOPA administration, a phenomenon that historically caused great confusion. In addition, -DOPA, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of restless leg syndrome. The two types of response seen with administration of -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

-DOPA is produced from the amino acid -
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
by the enzyme tyrosine hydroxylase. -DOPA can act as an -tyrosine mimetic and be incorporated into proteins by mammalian cells in place of L-tyrosine, generating
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
-resistant and aggregate-prone proteins ''in vitro'' and may contribute to neurotoxicity with chronic -DOPA administration. It is also the precursor for the monoamine or
catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol ( benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a ...
neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of -DOPA by aromatic -amino acid decarboxylase (AADC). -DOPA can be directly metabolized by catechol-''O''-methyl transferase to 3-''O''-methyldopa, and then further to vanillactic acid. This metabolic pathway is nonexistent in the healthy body, but becomes important after peripheral -DOPA administration in patients with Parkinson's disease or in the rare cases of patients with AADC enzyme deficiency. -Phenylalanine, -tyrosine, and -DOPA are all precursors to the biological
pigment A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic comp ...
melanin. The enzyme
tyrosinase Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxyl ...
catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of -DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relat ...
s. In addition,
tyrosinase Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxyl ...
can convert tyrosine directly to -DOPA in the presence of a reducing agent such as
ascorbic acid Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) a ...
.


Marine adhesion

-DOPA is a key compound in the formation of
marine adhesive protein Marine is an adjective meaning of or pertaining to the sea or ocean. Marine or marines may refer to: Ocean * Maritime (disambiguation) * Marine art * Marine biology * Marine debris * Marine habitats * Marine life * Marine pollution Military ...
s, such as those found in mussels. It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. -DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
. The versatile chemistry of L-DOPA can be exploited in nanotechnology. For example, DOPA-containing self-assembling peptides were found to form functional nanostructures, adhesives and gels.


Side effects and adverse reactions

The side effects of -DOPA may include: * Hypertension, especially if the dosage is too high * Arrhythmias, although these are uncommon *
Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, which is often reduced by taking the drug with food, although
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
reduces drug absorption. -DOPA is an amino acid, so protein competitively inhibits -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
emotion Emotions are mental states brought on by neurophysiological changes, variously associated with thoughts, feelings, behavioral responses, and a degree of pleasure or displeasure. There is currently no scientific consensus on a definition. ...
al states, particularly
anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil Turmoil may refer to: * ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte * ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...
, but also excessive
libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act ...
* Vivid
dream A dream is a succession of images, ideas, emotions, and sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around 5 to 20 minutes, al ...
s or
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...
* Auditory or visual hallucinations * Effects on learning; some evidence indicates it improves
working memory Working memory is a cognitive system with a limited capacity that can hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term memory, ...
, while impairing other complex functions * Somnolence and narcolepsy * A condition similar to stimulant psychosis Although many adverse effects are associated with -DOPA, in particular psychiatric ones, it has fewer than other
antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutri ...
s, such as
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...
s and dopamine receptor agonists. More serious are the effects of chronic -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 Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
) *
Dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor o ...
at peak dose ( levodopa-induced dyskinesia) * Possible dopamine dysregulation: The long-term use of -DOPA in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome. Clinicians try to avoid these side effects and adverse reactions by limiting -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 In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen ...
(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 intracellular 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 In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maint ...
.


History

In work that earned him a
Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfre ...
in 2000,
Swedish Swedish or ' may refer to: Anything from or related to Sweden, a country in Northern Europe. Or, specifically: * Swedish language, a North Germanic language spoken primarily in Sweden and Finland ** Swedish alphabet, the official alphabet used by ...
scientist Arvid Carlsson first showed in the 1950s that administering -DOPA to animals with drug-induced (
reserpine Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
) Parkinsonian
symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
s 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, published together with the neurologist
Walther Birkmayer Walther is a masculine given name and a surname. It is a German form of Walter, which is derived from the Old High German ''Walthari'', containing the elements ''wald'' -"power", "brightness" or "forest" and ''hari'' -"warrior". The name was firs ...
dramatic therapeutic antiparkinson effects of intravenously administered -DOPA in patients. This treatment was later extended to manganese poisoning and later Parkinsonism by
George Cotzias George Constantin Cotzias (June 16, 1918 – June 13, 1977) was a Greek scientist who together with his coworkers developed L-Dopa treatment, currently the most commonly used treatment for Parkinson's disease. Cotzias was born in Chania on the ...
and his coworkers, who used greatly increased oral doses, for which they won the 1969 Lasker Prize. The
neurologist Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
Oliver Sacks describes this treatment in human patients with
encephalitis lethargica Encephalitis lethargica is an atypical form of encephalitis. Also known as "sleeping sickness" or "sleepy sickness" (distinct from tsetse fly-transmitted sleeping sickness), it was first described in 1917 by neurologist Constantin von Econom ...
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. The 2001
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
was also related to -DOPA: the Nobel Committee awarded one-quarter of the prize to
William S. Knowles William Standish Knowles (June 1, 1917 – June 13, 2012) was an American chemist. He was born in Taunton, Massachusetts. Knowles was one of the recipients of the 2001 Nobel Prize in Chemistry. He split half the prize with Ryōji Noyori for thei ...
for his work on chirally catalysed
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate org ...
reactions, the most noted example of which was used for the synthesis of -DOPA. :


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 -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.


See also

* -DOPA (Dextrodopa) * -DOPS (Droxidopa) * Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.) *
Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
(Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.) *
Ciladopa Ciladopa (AY-27,110) is a dopamine agonist with a similar chemical structure to dopamine. It was under investigation as an antiparkinsonian agent but was discontinued due to concerns of tumorogenesis Carcinogenesis, also called oncogenesis ...
* Neuroleptic malignant syndrome * Melanin (a metabolite)


References


External links

* {{DEFAULTSORT:DOPA, L- Aromatic amino acids Antiparkinsonian agents Carbonic anhydrase activators Catecholamines Dopamine agonists Prodrugs Monoamine precursors