Absorption, Distribution and Excretion
A significant portion is absorbed (bioavailability evidence is insufficient). The primary route of excretion is the kidneys. Metabolism/Metabolites Primarily metabolized by the liver. Pergolitide undergoes extensive first-pass hepatic metabolism, with its metabolites primarily excreted in the urine. (A2932) Elimination Pathway: The primary route of excretion is the kidneys. Half-life: 27 hours. Biological Half-life 27 hours

Toxicity Summary
The dopamine D2 receptor is a 7-transmembrane G protein-coupled receptor associated with Gi proteins. In lactating cells, activation of the dopamine D2 receptor leads to inhibition of adenylate cyclase, thereby reducing intracellular cAMP concentration and blocking IP3-dependent release of Ca2+ from intracellular stores. The reduction in intracellular calcium levels may also be achieved by inhibiting calcium influx into voltage-gated calcium channels rather than by adenylate cyclase inhibition. Furthermore, receptor activation blocks p42/p44 MAPK phosphorylation and reduces MAPK/ERK kinase phosphorylation. MAPK inhibition appears to be mediated by c-Raf and β-Raf-dependent MAPK/ERK kinase inhibition. Dopamine-stimulated pituitary release of growth hormone is achieved not by inhibiting adenylate cyclase, but by reducing intracellular calcium ion influx mediated by voltage-gated calcium channels. Stimulation of dopamine D2 receptors in the nigrostriatal pathway can improve muscle coordination in patients with movement disorders. Ergoline alkaloids have been shown to have significant affinity for serotonin receptors (5-HT1 and 5-HT2), dopamine receptors (D1 and D2), and α-adrenergic receptors. This can lead to a variety of effects, including vasoconstriction, seizures, and hallucinations. Pergolitide is a potent dopamine receptor agonist. It directly stimulates postsynaptic dopamine receptors at D1 and D2 receptor sites in the nigrostriatal system. This can alleviate motor complications associated with Parkinson's disease. 5-HT2B and 5-HT1B receptor agonists are considered to contribute to pergolitide-related fibrosis and valvular heart disease. (A365, A2933, A2934, A2914, A2915, A2916)

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Hepatotoxicity
Pergolitide has been reported to cause elevated serum transaminases in a small number of patients, but these abnormalities are usually mild, asymptomatic, and resolve spontaneously, even without dose adjustment. Furthermore, pergolitide has been associated with a small number of clinically significant cases of acute liver injury, but its frequency, severity, clinical characteristics, and typical pattern of enzyme elevation are not well understood. Therefore, pergolitide may be a rare cause of clinically significant liver injury.
Probability Score: E (Unproven but suspected cause of clinically significant liver injury).

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Protein Binding
90%

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Toxicity Data
LD50: 15 mg/kg (oral, rat) (A308)

Pergolide is a diamine, a derivative of ergoline, in which the β-hydrogen at position 8 is replaced by a (methylthio)methyl group, and the hydrogen at position 6 of the piperidine nitrogen atom is replaced by a propyl group. It is a dopamine D2 receptor agonist, but also possesses properties of D1 and D2 receptor agonists. It was previously used in mesylate form to treat Parkinson's disease, but was withdrawn from the US and Canadian markets in 2007 due to the increased risk of valvular heart dysfunction. It is both an anti-Parkinson's disease drug and a dopamine agonist. It is a diamine, an organic heterotetracyclic compound, and a methyl sulfide. It is the conjugate base of Pergolide (1+). Pergolide is a long-acting dopamine agonist approved in 1982 for the treatment of Parkinson's disease. It is an ergoline derivative that acts on dopamine D2 and D3 receptors, α2 and α1 adrenergic receptors, and serotonin (5-HT) receptors. It was initially approved as adjunctive therapy to levodopa/carbidopa for the symptomatic treatment of Parkinson's syndrome. However, it was later found that pergolitide increased the risk of valvular heart disease. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007. Although pergolitide is still approved for human use in only a few countries, it is primarily used in veterinary medicine. Pergolitide is an ergot derivative dopamine receptor agonist. Its mechanism of action is as a dopamine agonist. Pergolitide is an oral dopamine receptor agonist primarily used to treat Parkinson's disease. Transient elevations of serum enzymes during pergolitide treatment are rare but have been associated with rare cases of acute liver injury. Pergolitide is a long-acting dopamine agonist approved for the treatment of Parkinson's disease in 1982. It is an ergot derivative that acts on dopamine D2 and D3 receptors, α2 and α1 adrenergic receptors, and serotonin (5-HT) receptors. It was previously approved in combination with levodopa/carbidopa for the symptomatic treatment of Parkinson's syndrome. However, it was later found that pergolitide increases the risk of valvular heart disease. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007. This is a long-acting dopamine agonist that was previously used to treat Parkinson's disease and hyperprolactinemia, but has been withdrawn from some markets due to its potential to cause valvular heart disease. See also: Pergolitide mesylate (in salt form).
Drug Indications Indicated as adjunctive therapy to levodopa/carbidopa for the treatment of signs and symptoms of Parkinson's disease. Due to the increased risk of valvular heart disease, the drug was withdrawn from the US and Canadian markets in 2007.
FDA Label

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Mechanism of Action
Dopamine D2 receptor is a 7-transmembrane G protein-coupled receptor associated with Gi protein. In lactating cells, activation of dopamine D2 receptor inhibits adenylate cyclase, thereby reducing intracellular cAMP concentration and blocking IP3-dependent release of intracellular Ca2+. The reduction in intracellular calcium levels may also be achieved by inhibiting calcium influx into voltage-gated calcium channels rather than inhibiting adenylate cyclase. Furthermore, receptor activation blocks phosphorylation of p42/p44 MAPK and reduces phosphorylation levels of MAPK/ERK kinases. MAPK inhibition appears to be mediated by c-Raf and β-Raf-dependent MAPK/ERK kinase inhibition. Dopamine-stimulated pituitary release of growth hormone is achieved by reducing intracellular calcium influx into voltage-gated calcium channels rather than inhibiting adenylate cyclase. Stimulation of dopamine D2 receptor in the substantia nigra-striatal pathway improves coordinated muscle activity in patients with movement disorders.

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Pharmacodynamics
Pergolitide stimulates central dopaminergic receptors, thereby producing a variety of pharmacological effects. Five dopamine receptors from two dopaminergic subfamilies have been identified. The dopamine D1 receptor subfamily, composed of D1 and D5 subreceptors, is associated with motor disorders. The dopamine D2 receptor subfamily, composed of D2, D3, and D4 subreceptors, is associated with the improvement of motor disorder symptoms. Therefore, specific agonist activity of D2 subfamily receptors (mainly D2 and D3 receptor subtypes) is a major target for dopaminergic anti-Parkinson's disease drugs. It is believed that stimulation of postsynaptic D2 receptors is the main reason for the anti-Parkinson's disease effect of dopamine agonists, while stimulation of presynaptic D2 receptors confers neuroprotective effects. This semi-synthetic ergot derivative exhibits potent agonist activity against both dopamine D2 and D3 receptors. It also exhibits agonist activity against dopamine D4, D1, and D5, serotonin (5-HT)1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, α2A-, α2B-, α2C-, α1A-, α1B-, and α1D-adrenergic receptors. Parkinson's disease occurs due to the loss of approximately 80% dopaminergic activity in the substantia nigra-striatal pathway of the brain. Since the striatum is involved in regulating and coordinating the intensity of muscle activity (e.g., movement, balance, walking), its loss of activity can lead to dystonia (acute muscle contractions), Parkinson's syndrome (including symptoms such as bradykinesia, tremor, rigidity, and apathy), akathisia (restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term dopaminergic loss), and neuroleptic malignancy, the latter occurring when dopamine in the substantia nigra-striatal pathway is completely blocked. Excessive dopaminergic activity in the limbic pathway of the brain can lead to hallucinations and delusions; these side effects of dopamine agonists are common in patients with schizophrenia because this area of their brain is overactive. The hallucinogenic side effects of dopamine agonists may also be related to 5-HT2A receptor agonism. The tuberous-infundibular pathway originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits the secretion of prolactin by the anterior pituitary lactocytes. Increased dopaminergic activity in the tuberous-infundibular pathway inhibits prolactin secretion. Pergolitide also causes a transient increase in growth hormone secretion and a decrease in luteinizing hormone (LH) concentration.

C19H26N2S

314.4881

314.181

66104-22-1

Pergolide mesylate;66104-23-2

47811

Typically exists as solid at room temperature

1.1±0.1 g/cm3

491.3±35.0 °C at 760 mmHg

207.5ºC

250.9±25.9 °C

0.0±1.2 mmHg at 25°C

1.614

4.49

1

2

4

22

388

3

S(C([H])([H])[H])C([H])([H])C1([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])[H])C2([H])C([H])([H])C3=C([H])N([H])C4=C([H])C([H])=C([H])C(=C34)C2([H])C1([H])[H]

YEHCICAEULNIGD-MZMPZRCHSA-N

InChI=1S/C19H26N2S/c1-3-7-21-11-13(12-22-2)8-16-15-5-4-6-17-19(15)14(10-20-17)9-18(16)21/h4-6,10,13,16,18,20H,3,7-9,11-12H2,1-2H3/t13-,16-,18-/m1/s1

(6aR,9R,10aR)-9-(methylsulfanylmethyl)-7-propyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)