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

44.33

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。