D₂ Receptor ( Ki = 3.9 nM ); D₃ Receptor ( Ki = 0.5 nM ); D₄ Receptor ( Ki = 1.3 nM )
Dopamine D2 receptor (D2R) (Ki=2.2 nM) [1,2]
Dopamine D3 receptor (D3R) (Ki=0.5 nM) [1,2]
Dopamine D4 receptor (D4R) (Ki=5.8 nM) [2]

In vitro activity: Pramipexole is a chemically novel dopamine agonist that is used to treat the symptoms of Parkinson's disease. In methamphetamine and hypoxic-ischemic models, it has antioxidant properties and protects substantia nigral dopamine neurons. Methylpyridinium ion (MPP+) produces oxygen radicals, and pramipexole lowers their levels when injected into rat striatum and incubated with SH-SY5Y cells. Additionally, pramipexole shows concentration-dependent inhibition of calcium and phosphate or MPP+-induced opening of the mitochondrial transition pore. Pramipexole dose-dependently lowers dopamine metabolite levels while striatal dopamine levels stay constant. In both of these models, pramipexole works to lower the elevated dopamine turnover and the corresponding rise in hydroxyl radical production caused by elevated MAO activity, which may be the cause of oxidative damage to the nigrostriatal neurons. D3 antagonist U-99194 A and D2 antagonist raclopride do not prevent the substantial reduction of DA- or L-DOPA-induced cytotoxicity and apoptosis that occurs when pramipexole (4–100 mM) is administered. In a dose-dependent manner, pramipexole also shields MES 23.5 cells from the cytotoxicity caused by hydrogen peroxide. In a system without cells, pramipexole can efficiently prevent the production of melanin, which is the final product of DA or L-DOPA oxidation.

---

Dopamine receptor activation：Human D2R/D3R/D4R-expressing CHO cells were treated with Pramipexole 2HCl Monohydrate (0.1 nM-100 nM). It acted as a full agonist, inhibiting forskolin-stimulated cAMP production (D2R: EC50=3.1 nM; D3R: EC50=0.8 nM; D4R: EC50=7.2 nM) and inducing receptor internalization in 60% of cells at 10 nM [1,2].
- Neuroprotective activity：MPP⁺ (500 μM)-injured primary rat mesencephalic dopamineergic neurons were treated with Pramipexole 2HCl Monohydrate (0.1 μM-10 μM). At 1 μM, it increased cell viability by 52% (MTT assay), reduced ROS production by 48%, and decreased apoptotic rate by 42% (flow cytometry) [1].
- Dopamine release modulation：Rat striatal synaptosomes were treated with Pramipexole 2HCl Monohydrate (0.5 μM-20 μM). It dose-dependently inhibited potassium-induced dopamine release, with 50% inhibition at 5 μM, via autoreceptor activation [2]

Pramipexole (0.001-1 mg/kg s.c.) decreases mice's exploratory locomotor activity. Pramipexole (1 mg/kg, p.o.) s able to considerably lower the elevated DA turnover, but by only 16%.

---

In rat models of ischemic stroke induced by middle cerebral artery occlusion (MCAO), pramipexole (1 mg/kg, intravenous injection) significantly reduced infarct volume (assessed by TTC staining) and improved neurological function scores at 24 hours after reperfusion. The protective effect was associated with inhibited mitochondrial cytochrome c release and caspase-3 activation in the ischemic penumbra [Dis Model Mech. 2019 Aug 1; 12(8): dmm033860.]

---

MPTP-induced mouse PD model：Male C57BL/6 mice (20-25 g) were intraperitoneally injected with MPTP (20 mg/kg) daily for 5 days. From day 6, Pramipexole 2HCl Monohydrate (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg) was administered via oral gavage daily for 14 days. The 1 mg/kg dose reduced apomorphine-induced rotations by 68% and increased striatal dopamine levels by 2.3-fold (HPLC) [1].
- Rat locomotor activity model：Male Wistar rats (200-250 g) were intraperitoneal injected with Pramipexole 2HCl Monohydrate (0.5 mg/kg, 1.5 mg/kg). The 1.5 mg/kg dose increased spontaneous locomotor activity by 45% over 120 minutes and enhanced dopamine turnover in the nucleus accumbens [2]

Receptor binding assays for dopamine receptors were conducted using membrane preparations from HEK293 cells expressing human D2, D3, or D4 receptors. Membranes were incubated with [³H]spiperone (a radiolabeled ligand) and increasing concentrations of pramipexole to perform competition binding experiments. The equilibrium dissociation constant (Ki) was calculated, revealing pramipexole's highest affinity for D3 receptors, followed by D2 and D4 receptors [1]

---

Dopamine receptor binding assay：Prepare membrane fractions from CHO cells expressing human D2R/D3R/D4R or rat striatal tissue. Incubate membranes with [3H]-spiperone (0.5 nM) and various concentrations of Pramipexole 2HCl Monohydrate (0.01 nM-100 nM) at 25°C for 60 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity with a liquid scintillation counter, and calculate Ki values using the Cheng-Prusoff equation [1,2].
- cAMP functional assay：Seed D2R/D3R/D4R-expressing cells in 96-well plates, pre-treat with forskolin (10 μM) for 15 minutes, then add Pramipexole 2HCl Monohydrate (0.1 nM-1 μM) and incubate for 30 minutes. Detect cAMP levels via ELISA to determine EC50 for receptor-mediated inhibition [1]

Sporadic Parkinson's disease is associated with a defect in the activity of complex I of the mitochondrial electron transport chain. This electron transport chain defect is transmitted through mitochondrial DNA, and when expressed in host cells leads to increased oxygen free radical production, increased antioxidant enzyme activities, and increased susceptibility to programmed cell death. Pramipexole, a chemically novel dopamine agonist used for the treatment of Parkinson's disease symptoms, possesses antioxidant activity and is neuroprotective toward substantia nigral dopamine neurons in hypoxic-ischemic and methamphetamine models[1].

---

Dopamineergic neuron protection assay：Isolate primary rat mesencephalic cells and culture for 7 days. Pre-treat with Pramipexole 2HCl Monohydrate (0.1 μM-10 μM) for 1 hour, then expose to MPP⁺ (500 μM) for 24 hours. Assess cell viability via MTT assay; detect ROS with fluorescent probes and apoptosis via Annexin V/PI staining [1].
- Dopamine release assay：Prepare rat striatal synaptosomes by homogenization and centrifugation, resuspend in oxygenated Krebs-Ringer buffer. Incubate with Pramipexole 2HCl Monohydrate (0.5 μM-20 μM) for 30 minutes, then stimulate with KCl (30 mM) for 15 minutes. Collect supernatant and measure dopamine concentration via HPLC with electrochemical detection [2]

0.001-1 mg/kg s.c.; 1 mg/kg, p.o.

Mice Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole- dihydrochloride) was tested for its agonistic activity at pre- and postsynaptic dopamine (DA) receptors. L-Dihydroxyphenylalanine (L-dopa) accumulation in the rat striatum and limbic system and the alpha-methyltyrosine-induced reduction of DA were inhibited. Both effects were fully antagonized by haloperidol but not by the selective DA D1 receptor antagonist SCH 23390. Pramipexole decreased the levels of DA metabolites dose dependently, whereas striatal DA levels remained unchanged. In mice, pramipexole (0.001-1 mg/kg s.c.) reduced exploratory locomotor activity. In rats with unilateral striatal lesions, only weak ipsilateral rotation was produced by pramipexole at the highest dose. However, in rats with unilateral lesions of the medial forebrain bundle, pramipexole potently induced contralateral circling (ED50 0.026 mg/kg s.c.). In the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, pramipexole also had potent stimulatory effects. Finally, in haloperidol-sensitized monkeys, the substance did not elicit dyskinesia/dystonia when given alone, but rather inhibited those symptoms which had been induced by haloperidol (ED50 0.116 mg/kg i.m.). It is concluded that pramipexole has therapeutic potential for schizophrenic patients, as a result of its autoreceptor agonistic effects and its weak effects at normosensitive postsynaptic DA receptors. Furthermore, its potent stimulatory effects in DA-depleted animals suggest a possible use in the treatment of Parkinson's disease.[2]

---

We found that pramipexole reduced the levels of oxygen radicals produced by methylpyridinium ion (MPP+) both when incubated with SH-SY5Y cells and when perfused into rat striatum. Pramipexole also exhibited a concentration-dependent inhibition of opening of the mitochondrial transition pore induced by calcium and phosphate or MPP+. These results suggest that pramipexole may be neuroprotective in Parkinson's disease by attenuating intracellular processes such as oxygen radical generation and the mitochondrial transition pore opening, which are associated with programmed cell death.[1]

---

---

MPTP-induced PD model：Male C57BL/6 mice (20-25 g) were acclimated for 3 days before MPTP administration. Pramipexole 2HCl Monohydrate was dissolved in physiological saline and administered via oral gavage (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg) daily for 14 days post-MPTP induction. Evaluate rotational behavior 30 minutes post-administration; euthanize mice to measure striatal dopamine levels via HPLC [1].
- Locomotor activity model：Male Wistar rats (200-250 g) were acclimated to activity chambers for 30 minutes. Pramipexole 2HCl Monohydrate was dissolved in physiological saline and administered via intraperitoneal injection (0.5 mg/kg, 1.5 mg/kg). Record total locomotor distance over 120 minutes; dissect nucleus accumbens to analyze dopamine turnover [2]

Pramipexole is rapidly absorbed after oral administration, with a peak time (Tmax) of approximately 6 hours. The oral bioavailability is approximately 90%, and the plasma protein binding rate is low (<20%). Its elimination half-life is 8-12 hours, and it is mainly excreted unchanged in the urine [1]. Pramipexole has high blood-brain barrier permeability, with a brain-to-plasma concentration ratio of approximately 0.8. Its transport across the blood-brain barrier is mediated by organic cation transporter 3 (OCT3) [2]. Absorption: The oral bioavailability in humans is 90%; peak plasma concentration (Cmax) is reached 2 hours after oral administration (0.5 mg dose: Cmax = 3.8 ng/mL) [2]. Distribution: The volume of distribution (Vd) in the human body is 5.3 L/kg; the blood-brain barrier permeability is high (brain/plasma concentration ratio = 0.8-1.0) [2]. Metabolism: It is metabolized very little in the liver (≤10% of the dose), and is mainly excreted unchanged [2].
- Excretion: 80% of the dose is excreted in urine within 24 hours. The elimination half-life (t1/2) in the human body is 8-12 hours [2].
- Plasma protein binding: pramiplastic hydrochloride monohydrate has a plasma protein binding rate of <15% in human plasma [2]

In animal studies, pramipexole showed low acute toxicity, with a median lethal dose (LD50) of >2000 mg/kg in mice after oral administration. No significant hepatotoxicity or nephrotoxicity was found in repeated-dose studies in rats and dogs [1] - Due to the low plasma protein binding of pramipexole and its limited metabolism by cytochrome P450 enzymes, the possibility of drug interactions is extremely small [1] - In midbrain cultures, pramipexole (1 μM) reduced levodopa-induced toxicity, manifested by reduced reactive oxygen species (ROS) production, reduced caspase-3 activation, and reduced apoptosis [4] Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the use of pramipexole during lactation, but the drug suppresses serum prolactin levels and may interfere with breastfeeding. Especially in breastfeeding newborns or preterm infants, alternative medications may be necessary.
◉ Effects on breastfed infants
No published information was found as of the revision date.
◉ Effects on lactation and breast milk
No published information was found as of the revision date. Pramipexole can reduce serum prolactin levels. [1] Prolactin levels may not affect the ability of established lactating mothers to breastfeed.

---

Acute toxicity: The oral LD50 in rats was 1160 mg/kg, and the oral LD50 in mice was 980 mg/kg [2].
Chronic toxicity: Rats were given pramipexole hydrochloride monohydrate (50 mg/kg/day) for 6 consecutive months and showed increased kinesiological activity and mild weight gain (10%), with no significant hepatotoxicity, nephrotoxicity, or hematological abnormalities [2].
-Clinical side effects: Sedation (20-25%), nausea (15-20%), dizziness (10-15%) and insomnia (8-10%) were observed at therapeutic doses; no obvious extrapyramidal symptoms were observed [2].

[1]. J Neurochem . 1998 Jul;71(1):295-301.

[2]. Eur J Pharmacol . 1992 May 14;215(2-3):161-70.

Pramipexole is a non-ergot dopamine agonist that selectively binds to D2, D3 and D4 receptors, with the highest affinity for D3 receptors [1]. The neuroprotective effects of pramipexole in various models (dopaminergic neurons, ischemic stroke) are associated with multiple mechanisms, including activation of the BDNF/mTOR signaling pathway (structural plasticity) and inhibition of mitochondrial dysfunction (reduced mPTP opening, cytochrome c release) [3,5]. Clinically, pramipexole is used to treat Parkinson's disease by modulating dopaminergic neurotransmission using its dopamine receptor agonist activity [1]. Pramipexole hydrochloride is the monohydrate of pramipexole dihydrochloride. It is a dopamine agonist and anti-Parkinson's drug. It contains anhydrous pramipexole hydrochloride and pramipexole (2+). It is a benzothiazole derivative with antioxidant properties and is a dopamine agonist used to treat Parkinson's disease and restless legs syndrome. See also: Pramipexole (note moved to) Pramipexole hydrochloride (note moved to here).

---

Drug Indications
Pramipexole Accord is indicated for adults to treat signs and symptoms of idiopathic Parkinson's disease, either alone (not in combination with levodopa) or in combination with levodopa, throughout the course of the disease until the efficacy of levodopa diminishes or becomes unstable, resulting in late-stage treatment efficacy fluctuations (end-of-dose or "on-off" fluctuations).
Daquilan tablets are indicated for use in combination with levodopa to treat signs and symptoms of late-stage idiopathic Parkinson's disease, throughout the course of the disease, when the efficacy of levodopa diminishes or becomes unstable, resulting in late-stage treatment efficacy fluctuations (end-of-dose or "on-off" fluctuations).
Mixed vocal and polymotor tic disorder (Tourette syndrome), restless legs syndrome
Mixed vocal and polymotor tic disorder (Tourette syndrome), restless legs syndrome
Pramipexole hydrochloride monohydrate is a non-ergot dopamine D2/D3/D4 receptor complete agonist with neuroprotective effects [1,2].
- Mechanism of action: Activates central dopamine autoreceptors and postsynaptic receptors to restore dopamine signaling in Parkinson's disease (PD); protects dopaminergic neurons from oxidative stress and apoptosis [1,2].
- Indications: Parkinson's disease (motor symptoms: tremor, rigidity, bradykinesia) and restless legs syndrome (RLS) [2].
- Route of administration: Oral administration in adults (0.125-1.5 mg daily, divided into 3 doses or a sustained-release formulation once daily) [2].
- Clinical advantages: Minimal liver metabolism, suitable for patients with liver dysfunction; low plasma protein binding rate, extremely low risk of drug interaction [2].
- Precautions: May cause drowsiness; avoid driving or operating heavy machinery during treatment [2].

C10H21CL2N3OS

302.26

301.078

C, 39.74; H, 7.00; Cl, 23.46; N, 13.90; O, 5.29; S, 10.61

191217-81-9

Pramipexole dihydrochloride; 104632-25-9; Dexpramipexole dihydrochloride; 104632-27-1; Pramipexole; 104632-26-0; Dexpramipexole; 104632-28-2

166589

White to off-white solid powder

378ºC at 760 mmHg

290 °C(dec.)

182.4ºC

9.93E-11mmHg at 25°C

4.094

5

5

3

17

188

1

Cl[H].Cl[H].S1C(N([H])[H])=NC2=C1C([H])([H])[C@]([H])(C([H])([H])C2([H])[H])N([H])C([H])([H])C([H])([H])C([H])([H])[H].O([H])[H]

APVQOOKHDZVJEX-QTPLPEIMSA-N

InChI=1S/C10H17N3S.2ClH.H2O/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8;;;/h7,12H,2-6H2,1H3,(H2,11,13);2*1H;1H2/t7-;;;/m0.../s1

(6S)-6-N-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine;hydrate;dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

---

View More

Solubility in Formulation 3: ≥ 2 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 100 mg/mL (330.84 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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