Dopamine receptor

体外活性：左旋多巴在 25-200 μM 浓度下，在胎鼠中脑培养物中产生剂量依赖性的 3H-DA 摄取减少。左旋多巴会导致活细胞和酪氨酸羟化酶 (TH) 阳性神经元数量减少，并破坏整个神经炎网络。在缺乏多巴胺的情况下，左旋多巴通过过度抑制壳核-苍白球 (GPe) 投射的神经元以及随后对苍白球 (GPe) 的去抑制来诱发运动障碍。左旋多巴导致苍白球 (GPi) 中细胞色素氧化酶信使 RNA 表达减少。

左旋多巴会引起由神经毒素 MPTP 诱发的帕金森病猴子出现多种异常运动。左旋多巴给药导致 6-OHDA 损伤大鼠 CdPu 中多巴胺 D3 受体表达的异位诱导。左旋多巴 (50 mg/kg) 通过激活完整大鼠的多巴胺 D1/D2 受体，增加整个基底神经节的 anandamide 浓度。左旋多巴在病变大鼠中产生越来越严重的口舌不自主运动，这种运动被大麻素激动剂 R(+)-WIN55,212-2 (1 mg/kg) 减弱。左旋多巴给药可逆转严重病变大鼠中 D2 多巴胺受体的上调，这提供了左旋多巴在基底神经节达到生物活性浓度的证据。

左旋多巴是一种用于帕金森病（PD）患者的多巴胺（DA）前体，在25-200 x 10（-6）M的浓度下，会导致胎鼠中脑培养物中3H-DA摄取的剂量依赖性减少。此外，在培养基中醌水平升高的同时，观察到活细胞和酪氨酸羟化酶（TH）阳性神经元数量的减少，以及整个神经网络的破坏。抗坏血酸（AA）消除了醌的过度生产，部分阻止了这些影响。尽管左旋多巴在体内的神经毒性尚未得到证实，但AA可能会降低PD患者内源性或移植DA神经元的脆弱性[1]。

7-week-old C57BL/6J mice
20 mg/kg
Orally

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Animal Surgery and Treatments. Wistar male rats (180–200 g, Iffa Credo) were anesthetized with pentobarbital (50 mg/kg, i.p.) and infused over 8 min with 6-OHDA (8 μg in 4 μl of 0.05% ascorbic acid in saline) at coordinates A = −3.8 mm, L = 1.5 mm, H = −8.5 mm. Three weeks later, they received twice a day, and for various periods of time, i.p. injections of vehicle, levodopa (in all experiments as l-DOPA methyl ester, 50 mg/kg, in combination with benserazide, a peripheral dopa decarboxylase inhibitor, 12.5 mg/kg) or levodopa plus SCH 23390 (0.5 mg/kg) or plus SKF 38393 (10 mg/kg), bromocriptine (10 mg/kg), quinpirole (0.1 mg/kg).[3]

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The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of Delta 9-tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this beneficial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate-putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors. In 6-OHDA-lesioned rats, anandamide levels were significantly reduced in the caudate-putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R(+)-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB1 receptor antagonist rimonabant (SR141716A). These results indicate that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors.[4]

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Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.[5]

Absorption, Distribution and Excretion
Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.
After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine
168L for orally inhaled levodopa.
Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.
...DRUG...MAY APPEAR IN MILK.
AFTER IP INJECTION INTO MICE, BIOTRANSFORMATION OF 60% OF RADIOACTIVELY LABELLED DL-DOPA TAKES PLACE WITHIN 10 MIN, & PEAK DOPAMINE LEVELS ARE REACHED 20 MIN AFTER ADMIN. ...APPROX 0.1% OF DOSE WAS PRESENT IN THE BRAIN AS (14)C-L-DOPA OR (14)C-DOPAMINE. /DL-DOPA/
MORE THAN 95% OF LEVODOPA IS DECARBOXYLATED IN PERIPHERY BY WIDELY DISTRIBUTED EXTRACEREBRAL AROMATIC L-AMINO ACID DECARBOXYLASE. ...LITTLE UNCHANGED DRUG REACHES CEREBRAL CIRCULATION & PROBABLY LESS THAN 1% PENETRATES INTO CNS.
MOST IS CONVERTED TO DOPAMINE... DOPAMINE METABOLITES ARE RAPIDLY EXCRETED IN URINE, ABOUT 80% OF RADIOACTIVELY LABELED DOSE BEING RECOVERED WITHIN 24 HR. ... THESE METABOLITES /3,4-DIHYDROXYPHENYLACETIC ACID & 3-METHOXY-4-HYDROXYPHENYLACETIC ACID/, AS WELL AS SMALL AMT OF LEVODOPA & DOPAMINE, ALSO APPEAR IN CEREBROSPINAL FLUID.
For more Absorption, Distribution and Excretion (Complete) data for LEVODOPA (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Levodopa is either converted to dopamine by aromatic-L-amino-acid decarboxylase or O-methylated to 3-O-methyldopa by catechol-O-methyltransferase. 3-O-methyldopa cannot be metabolized to dopamine. Once levodopa is converted to dopamine, it is converted to sulfated or glucuronidated metabolites, epinephrine E, or homovanillic acid through various metabolic processes. The primary metabolites are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%).
MOST IS CONVERTED TO DOPAMINE... BIOTRANSFORMATION OF DOPAMINE PROCEEDS RAPIDLY...EXCRETION PRODUCTS, 3,4-DIHYDROXYPHENYLACETIC ACID...& 3-METHOXY-4-HYDROXYPHENYLACETIC ACID... SOME BIOCHEMICAL EVIDENCE INDICATES THAT ACCELERATION OF LEVODOPA METABOLISM OCCURS DURING PROLONGED THERAPY, POSSIBLY DUE TO ENZYME INDUCTION.
MORE THAN 95%...IS DECARBOXYLATED...BY...AROMATIC L-AMINO ACID DECARBOXYLASE. ... A SMALL AMT /OF L-DOPA/ IS METHYLATED TO 3-O-METHYL-DOPA... MOST IS CONVERTED TO DOPAMINE, SMALL AMT OF WHICH IN TURN ARE METABOLIZED TO NOREPINEPHRINE & EPINEPHRINE.
...IS ESTIMATED THAT ABOUT THREE FOURTHS OF DIETARY METHIONINE IS UTILIZED FOR METABOLISM OF LARGE THERAPEUTIC DOSES OF LEVODOPA.
LEVODOPA (L-DOPA) IS FORMED IN MAMMALS FROM L-TYROSINE AS INTERMEDIARY METABOLITE IN ENZYMATIC SYNTHESIS OF CATECHOLAMINES.
95% of an administered oral dose of levodopa is pre-systemically decarboxylated to dopamine by the L-aromatic amino acid decarboxylase (AAAD) enzyme in the stomach, lumen of the intestine, kidney, and liver. Levodopa also may be methoxylated by the hepatic catechol-O-methyltransferase (COMT) enzyme system to 3-O-methyldopa (3-OMD), which cannot be converted to central dopamine.
Half Life: 50 to 90 minutes

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Biological Half-Life
2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours.
THE HALF-LIFE IN PLASMA IS SHORT (1-3 HR).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited data indicate that levodopa is poorly excreted into breastmilk and that the sustained-release product may result in a smaller amount of drug transferred to the breastfed infant than with the immediate-release product. Several studies indicate that levodopa can decrease serum prolactin during lactation. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. The effect of long-term use of levodopa on breastfeeding has not been adequately evaluated, although some mothers were able to successfully breastfeed her infant without apparent harm while using relatively low doses of levodopa and carbidopa for Parkinson's disease.
◉ Effects in Breastfed Infants
One mother with Parkinson's disease took sustained-release levodopa 200 mg and carbidopa 50 mg 4 times daily. She successfully breastfed her infant whose development was normal at 2 years of age.
A 37-year-old Israeli woman with Parkinson's disease became pregnant while taking a continuous infusion of levodopa 20 mg/mL and carbidopa 5 mg/mL gel. She breastfed her infant for 3 months while receiving the drug, although the extent of breastfeeding and the dosage of the gel is not clear from the paper. At 10 months of age, the infant's psychomotor development was deemed to be normal.
◉ Effects on Lactation and Breastmilk
Levodopa decreases serum prolactin in normal women and those with hyperprolactinemia and can suppress inappropriate lactation in galactorrhea, although not consistently. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
One mother with Parkinson's disease took sustained-release levodopa 200 mg and carbidopa 50 mg 4 times daily. She successfully breastfed her infant.
On postpartum day 3, 5 women were given a single oral dose of 500 mg of levodopa or bromocriptine 5 mg followed by a single oral dose of metoclopramide 10 mg 3 hours later. Bromocriptine suppressed basal serum prolactin to a greater extent than levodopa. Over the next 3 hours, serum prolactin increased after metoclopramide in the patients who received levodopa, but not in those who received bromocriptine.
Six women who were 2 to 4 days postpartum, but were not nursing, were given 500 mg of levodopa orally on one day and 100 mg of levodopa plus 35 mg of carbidopa orally on the next day. Both regimens suppressed basal serum prolactin levels. However, levodopa alone caused an 78% decrease in prolactin while the lower dose combination produced only a 51% decrease. The maximal effect occurred about 2 hours after the dose with both regimens.
Seven women in the first week postpartum who were breastfeeding about 7 times daily were given levodopa 500 mg orally and their serum prolactin responses was studied. The following day, they started carbidopa 50 mg orally every 6 hours for 2 days. On the third day, they received a single dose of carbidopa 50 mg plus levodopa 125 mg orally. Decreases in basal serum prolactin occurred by 30 minutes after the levodopa and after 45 minutes with the combination. Decreases were maximum at 120 minutes after the dose and were 62% with levodopa alone and 48% with the combination, although the difference between the 2 regimens was not statistically significant.
A 37-year-old Israeli woman with Parkinson's disease became pregnant while taking a continuous infusion of levodopa 20 mg/mL and carbidopa 5 mg/mL gel. She breastfed her infant for 3 months while receiving the drug, although the extent of breastfeeding and the dosage of the gel is not clear from the paper.

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Protein Binding
Levodopa binding to plasma proteins is negligible.

[1]. Neuroreport . 1993 Apr;4(4):438-40.

[2]. J Antimicrob Chemother . 2004 Jun;53(6):1086-9.

[3]. Proc Natl Acad Sci U S A, 1997, 94(7), 3363-3367.

[4]. Eur J Neurosci . 2003 Sep;18(6):1607-14.

[5]. Ann Neurol . 1998 May;43(5):561-75.

Levodopa can cause developmental toxicity according to state or federal government labeling requirements.
L-dopa is an optically active form of dopa having L-configuration. Used to treat the stiffness, tremors, spasms, and poor muscle control of Parkinson's disease It has a role as a prodrug, a hapten, a neurotoxin, an antiparkinson drug, a dopaminergic agent, an antidyskinesia agent, an allelochemical, a plant growth retardant, a human metabolite, a mouse metabolite and a plant metabolite. It is a dopa, a L-tyrosine derivative and a non-proteinogenic L-alpha-amino acid. It is a conjugate acid of a L-dopa(1-). It is an enantiomer of a D-dopa. It is a tautomer of a L-dopa zwitterion.
Levodopa is a prodrug of dopamine that is administered to patients with Parkinson's due to its ability to cross the blood-brain barrier. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrier. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson's. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 1975.
3,4-Dihydroxy-L-phenylalanine is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
Levodopa is an Aromatic Amino Acid.
Levodopa has been reported in Mucuna macrocarpa, Amanita muscaria, and other organisms with data available.
Levodopa is an amino acid precursor of dopamine with antiparkinsonian properties. Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. When in the brain, levodopa is decarboxylated to dopamine and stimulates the dopaminergic receptors, thereby compensating for the depleted supply of endogenous dopamine seen in Parkinson's disease. To assure that adequate concentrations of levodopa reach the central nervous system, it is administered with carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, thereby diminishing the decarboxylation and inactivation of levodopa in peripheral tissues and increasing the delivery of dopamine to the CNS.
L-Dopa is used for the treatment of Parkinsonian disorders and Dopa-Responsive Dystonia and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Peripheral tissue conversion may be the mechanism of the adverse effects of levodopa. It is standard clinical practice to co-administer a peripheral DOPA decarboxylase inhibitor - carbidopa or benserazide - and often a catechol-O-methyl transferase (COMT) inhibitor, to prevent synthesis of dopamine in peripheral tissue.
The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [PubChem]

L-Dopa is the naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, L-Dopa can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. In particular, it is metabolized to dopamine by aromatic L-amino acid decarboxylase. Pyridoxal phosphate (vitamin B6) is a required cofactor for this decarboxylation, and may be administered along with levodopa, usually as pyridoxine.
The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.
See also: Melevodopa (is active moiety of); Carbidopa; Levodopa (component of); Carbidopa; entacapone; levodopa (component of) ... View More ...

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Drug Indication
Levodopa on its own is formulated as an oral inhalation powder indicated for intermittent treatment of off episodes in Parkinson's patients who are already being treated with carbidopa and levodopa. Levodopa is most commonly formulated as an oral tablet with a peripheral dopa decarboxylase inhibitor indicated for treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication.
FDA Label
Inbrija is indicated for the intermittent treatment of episodic motor fluctuations (OFF episodes) in adult patients with Parkinson's disease (PD) treated with a levodopa/dopa-decarboxylase inhibitor.
Treatment of Parkinson's disease

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Mechanism of Action
Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors.
MOST WIDELY ACCEPTED THEORY IS THAT LEVODOPA INCR LEVEL OF DOPAMINE & THUS ACTIVATION OF DOPAMINE RECEPTORS IN EXTRA-PYRAMIDAL CENTERS IN THE BRAIN (PRIMARILY IN CAUDATE NUCLEUS & SUBSTANTIA NIGRA).
The present data indicate that the major effects observed after administration of exogenous levodopa are not due to a direct action of levodopa on dopamine receptors, or to extrastriatal release of dopamine, but to conversion of levodopa to dopamine by serotonergic terminals and probably some intrastriatal cells.
EFFECTS OF LEVODOPA ON HUMAN & MURINE MELANOMA CELLS EXAMINED. WHEN EXPONENTIALLY GROWING CELLS WERE EXPOSED TO L-DOPA, CHARACTERISTIC INHIBITION OF THYMIDINE INCORPORATION OBSERVED.
IN RATS, DOPAMINERGIC AGONISTS ALL CAUSED DECR IN SERUM PROLACTIN LEVELS.

C9H11NO4

197.19

197.068

C, 54.82; H, 5.62; N, 7.10; O, 32.46

59-92-7

L-DOPA-2,5,6-d3; 53587-29-4; L-DOPA-d6; 713140-75-1; L-DOPA sodium; 63302-01-2; L-DOPA-13C6; 201417-12-1; L-DOPA-13C; 586971-29-1

6047

White to off-white solid powder

1.5±0.1 g/cm3

448.4±45.0 °C at 760 mmHg

276-278 °C(lit.)

225.0±28.7 °C

0.0±1.1 mmHg at 25°C

1.655

-0.22

103.78

4

5

3

14

209

1

O([H])C1=C(C([H])=C([H])C(=C1[H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])[H])O[H]

WTDRDQBEARUVNC-LURJTMIESA-N

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

(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 3.33 mg/mL (16.89 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。 (<60°C).

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