|Biological half-life||0.75–1.5 hours|
|Chemical and physical data|
|Molar mass||197.19 g/mol|
|3D model (JSmol)|
L-DOPA (), also known as levodopa () or L-3,4-dihydroxyphenylalanine is an amino acid that is made and used as part of the normal biology of humans, some animals and plants. Some animals and humans make it via biosynthesis from the amino acidL-tyrosine. L-DOPA is the precursor to the neurotransmittersdopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS.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, Stalevo, Madopar, and Prolopa. 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).
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 made practical and proven clinically by George Cotzias and his coworkers, for which they won the 1969 Lasker Prize. Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzymearomatic 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.
Besides the central nervous system, L-DOPA is also converted into dopamine from within the peripheral nervous system. Excessive peripheral dopamine signaling 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 (Aton Pharma)Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), 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. 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, has been investigated as a potential treatment for restless leg syndrome. However, studies have demonstrated "no clear picture of reduced symptoms".
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.
L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase. 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 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.
L-Phenylalanine, L-tyrosine, and L-DOPA are all precursors to the biological pigmentmelanin. The enzyme tyrosinasecatalyzes 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.
The side effects of L-DOPA may include:
- Hypotension, 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:
Clinicians try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.
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, published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered L-DOPA in patients. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers, who used greatly increased oral doses. The neurologistOliver 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-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.
- Synthesis of L-DOPA via hydrogenation with C2-symmetric diphosphine.
Herbal extracts containing L-DOPA are available; high-yielding sources include Mucuna pruriens (velvet bean), and Vicia faba (broad bean), while other sources include the genera Phanera, Piliostigma, Cassia, Canavalia, and Dalbergia.
L-DOPA is a key compound in the formation of marineadhesiveproteins, 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.
Age-related macular degeneration
In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking vs. not taking L-DOPA found that the drug delayed onset of AMD by ~8 years. The authors state that significant effects were obtained for both dry and wet AMD.[non-primary source needed]
- D-DOPA (Dextrodopa)
- L-DOPS (Droxidopa)
- Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
- Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
- Neuroleptic malignant syndrome
- ^Citation; Lopez, VM; Decatur, CL; Stamer, WD; Lynch, RM; McKay, BS (2008). "L-DOPA is an endogenous ligand for OA1". PLoS Biol. 6 (9): e236. doi:10.1371/journal.pbio.0060236. PMC 2553842. PMID 18828673.
- ^Hiroshima Y1, Miyamoto H; Nakamura, F; et al. (Jan 2014). "The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii". Br J Pharmacol. 171 (2): 403–14. doi:10.1111/bph.12459.
- ^Jürgen Martens, Kurt Günther, Maren Schickedanz: "Resolution of Optical Isomers by Thin-Layer Chromatography: Enantiomeric Purity of Methyldopa", Arch. Pharm. (Weinheim) 1986, 319, S. 572−574. (DOI:10.1002/ardp.19863190618)
- ^Lasker Award 1969 Description, accessed April 1, 2013
- ^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
- ^"Medicare D". Medicare. 2014. Retrieved 12 November 2015.
- ^"Lodosyn", Drugs, nd, retrieved 12 November 2012
- ^"L-dopa for RLS". Bandolier. 1 April 2007. Archived from the original on 3 September 2012. Retrieved 2008-10-16.
- ^Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
- ^Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.
- ^Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
- ^Hyland K, Clayton PT (December 1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology"(PDF). Clinical Chemistry. 38 (12): 2405–10. PMID 1281049.
- ^Ito, S; Kato, T; Shinpo, K; Fujita, K. "Oxidation of tyrosine residues in proteins by tyrosinase. Formation of protein-bonded 3,4-dihydroxyphenylalanine and 5-S-cysteinyl-3,4-dihydroxyphenylalanine". Biochem J. 222: 407–11. PMC 1144193. PMID 6433900.
- ^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.
- ^EHRINGER H, HORNYKIEWICZ O (1960). "Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system". Klin Wochenschr. 38: 1236–9. PMID 13726012.
- ^BIRKMAYER W, HORNYKIEWICZ O (1961). "The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia". Wien Klin Wochenschr. 73: 787–8. PMID 13869404.
- ^Cotzias GC, Papavasiliou PS, Gellene R (1969). "L-dopa in parkinson's syndrome". The New England Journal of Medicine. 281 (5): 272–273. doi:10.1056/NEJM196907312810518. PMID 5791298.
- ^Knowles, William S. (1983). "Asymmetric hydrogenation". Accounts of Chemical Research. 16 (3): 106–112. doi:10.1021/ar00087a006.
- ^"Synthetic scheme for total synthesis of DOPA, L- (Monsanto)". UW Madison, Department of Chemistry. Retrieved Sep 30, 2013.
- ^Knowles, W. S. (March 1986). "Application of organometallic catalysis to the commercial production of L-DOPA". Journal of Chemical Education. 63 (3): 222. doi:10.1021/ed063p222.
- ^Pankaj Oudhia. "Kapikachu or Cowhage". Retrieved Nov 3, 2013.
- ^Ingle, PK (May–June 2003). "L-DOPA bearing plants". Natural Product Radiance. 2 (3): 126–133.
- ^Waite, J. Herbert; Andersen, Niels Holten; et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion. 81 (3–4): 1–21. doi:10.1080/00218460590944602.
- ^"Study Reveals Details Of Mussels' Tenacious Bonds". Science Daily. Aug 16, 2006. Retrieved Sep 30, 2013.
- ^Mussel Adhesive Protein MimeticsArchived 2006-05-29 at the Wayback Machine.
- ^Brilliant, Murray H.; Vaziri, Kamyar; Connor, Thomas B.; Schwartz, Stephen G.; Carroll, Joseph J.; McCarty, Catherine A.; Schrodi, Steven J.; Hebbring, Scott J.; Kishor, Krishna S.; Flynn, Harry W.; Moshfeghi, Andrew A.; Moshfeghi, Darius M.; Fini, M Elizabeth; McKay, Brian S. (October 2015). "Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration". The American Journal of Medicine. 129: 292–8. doi:10.1016/j.amjmed.2015.10.015. PMC 4841631. PMID 26524704.
Known also as dimethyltryptamine. DMT is a naturally occuring psychedelic of the tryptamine family. It is present in many plants & mammals, and is available for recreational use. Chemically known as dimethyltryptamine, it is structurally related to the neurotransmitter serotonin, the hormone melatonin, and the psychedelic compound psilocybin.
DMT products are consumed primarily for their psychedelic, hallucinogenic, or entheogenic properties. When combined with an MAOI to facilitate oral absorbtion, DMT is the main constituent in ayahuasca; a beverage consumed in Amazonian circles for entheogenic purposes.
DMT produces intense and short acting effects when smoked. Dosages commonly range from 2-60 milligrams (smoked).
Its mode of action is complex. DMT is known to act as a non selective agonist at multiple serotonergic receptors. It also interacts with dopaminergic, adrenergic, sigma, and trace amine associated (TAAR) receptors, with varying profiles of efficacy.
Also known as alpha-methyltryptamine. AMT is a synthetically produced psychedelic of the tryptamine family, also related to DMT. Its effects are relatively long lasting, and recommended dosages are slightly higher than those for DMT.
AMT produces both psychedelic and stimulant effects. In addition to its action as a non-selective 5HT receptor agonist, AMT acts as a monoamine releasing agent (that is, it induces synaptic release of dopamine, noradrenaline, and serotonin).
AMT is chemically related to tryptamine in the same way amphetamine is related to phenethylamine; with the addition of an alpha methyl group on the alkyl chain. AMT differs chemically from DMT in two ways; a) a secondary amine rather than a tertiary amine, and b) the aforementioned CH3 group at the alpha carbon.
AMT is commonly smoked or consumed orally. Its effects can take up to 2 hours to become fully apparent, and may last 12 hours or more when high doses are consumed. Nausea and vomiting has been commonly reported.
Psilocybin is a naturally occurring psychedelic compound which is present in 200 or more species of mushrooms. Psilocybin containing mushrooms are popularly known as "magic mushrooms". Magic mushrooms grow naturally in the US and elsewhere, or, may be artificially cultivated indoors.
Psilocybin is a drug of the tryptamine family, chemically related to DMT as well as the endogenous neurotransmitter, serotonin.
Psilocybin is rapidly metabolized to psilocin via dephosphorylation, with psilocin being mainly responsible for its effects. Psilocin targets the brain's serotonergic pathways, acting as an agonist at the 5HT2A receptor, as well as other subtypes, to a lesser extent.
Known chemically as methylisopropyltryptamine, MiPT is a psychoactive compound related to other tryptamines such as DMT and DiPT.
It was mentioned in Alexander Shulgin's book TIHKAL.
MiPT is reported to affect auditory perception and cognition more so than visual perception.
Analogues of MiPT have been marketed as research chemicals in recent years.DiPT
Known chemically as diisopropyltryptamine, DiPY is a psychedelic tryptamine related to both DMT and MiPT.
Users have reported marked changes in auditory perception with the experience.
Numerous analogues of DiPT have been marketed as research chemicals.
Known chemically as N,N-diallyltryptamine. DALT is a psychedelic tryptamine related to DMT, MiPT, and DiPT.
It was mentioned in Shulgin's book TIHKAL, and numerous analogues of this compound have appeared for sale as research chemicals.
Also known as O-acetylpsilocin. 4-ACO-DMT is a psychoactive compound of the tryptamine family. It is a ring substituted homologue of DMT, related to psilocybin and psilocin (the magic mushroom alkaloids). 4-ACO-DMT is an RC and is usually prepared synthetically, but like psilocybin, it acts as a prodrug for psilocin.