D3 recepto ( Ki = 0.5 nM ); D2L Receptor ( Ki = 2.2 nM ); D2S Receptor ( Ki = 3.9 nM ); D4 receptor ( Ki = 5.1 nM )

- In human iPSC-derived dopaminergic neurons, pramipexole (1 μM) promoted structural plasticity, as evidenced by increased neurite outgrowth and synapse formation (assessed via immunocytochemical staining for β-tubulin III and synapsin I). This effect was mediated by upregulation of BDNF and activation of mTOR signaling pathways, confirmed by western blot analysis showing elevated BDNF protein levels and phosphorylated mTOR [3]
- In mesencephalic cultures, pramipexole (1 μM) attenuated levodopa-induced toxicity. It reduced reactive oxygen species (ROS) production and caspase-3 activation, leading to increased cell viability (measured by MTT assay) compared to levodopa-alone treatment [4]
- In in vitro models of ischemic stroke, pramipexole (10 μM) prevented ischemic cell death by inhibiting mitochondrial permeability transition pore (mPTP) opening and maintaining mitochondrial membrane potential (ΔΨm). This was verified via JC-1 staining (for ΔΨm) and western blot analysis showing reduced cytochrome c release from mitochondria [5]
Pramipexole dihydrochloride has a low binding affinity for D1-type receptors [1]. Pramipexole dihydrochloride (0.01-10 μM; 72 hours) increases soma cell size and dendritic structures proportionate to the dose. Pramipexole HCl reduces the toxicity caused by levodopa in cultures of the midbrain, suggesting that Pramipexole HCl may protect dopamine neurons in tissue culture [4].

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 [5]
Pramipexole hydrochloride (0.25-1 mg/kg; ip) considerably lowers the volume of the infarct in animals. Pramipexole hydrochloride enhances neurological healing. Through pathways, pramipexole hydrochloride prevents AIDS-induced cell death in stroke.

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]
The blood-brain barrier (BBB) transport of pramipexole, a potent dopamine receptor agonist with high efficacy for Parkinson's disease, was mainly characterized using immortalized rat brain capillary endothelial cells (RBEC)1 as an in vitro BBB model. [(14)C]Pramipexole uptake by RBEC1 was dependent on temperature and pH, but not sodium ion concentration or membrane potential. The uptake was inhibited by several organic cations including pyrilamine. Mutual inhibition was observed between pramipexole and pyrilamine. In addition, [(14)C]pramipexole uptake was stimulated by preloading unlabeled pramipexole. RT-PCR analysis for organic cation transporters (rOCT1-3, rOCTN1-2) in RBEC1 was performed. The mRNA level of rOCTN2 was the highest, followed by rOCTN1, while expression of rOCT1, rOCT2 and rOCT3 was negligible. The brain uptake of [(14)C]pramipexole, which was measured by the in situ rat brain perfusion technique, was significantly inhibited by unlabeled pramipexole. These results suggest that pramipexole is, at least in part, transported across the BBB by an organic cation-sensitive transporter. The pramipexole transport in RBEC1 was pH-dependent, but sodium- and membrane potential-independent[2].

- For analyzing structural plasticity in human iPSC-derived dopaminergic neurons: Cells were treated with pramipexole (1 μM) for 24 hours. Neurite outgrowth and synapse formation were evaluated via immunocytochemical staining with antibodies against β-tubulin III (neuronal marker) and synapsin I (synaptic marker). Western blot was used to measure protein levels of BDNF and phosphorylated mTOR [3]
- For assessing levodopa-induced toxicity in mesencephalic cultures: Cultures were treated with levodopa (100 μM) alone or in combination with pramipexole (1 μM) for 48 hours. Cell viability was determined by MTT assay, and apoptosis was detected via Annexin V-FITC/PI staining followed by flow cytometry to quantify apoptotic cells [4]
- For investigating mitochondrial mechanisms in ischemic cell models: Cells were exposed to ischemic conditions and treated with pramipexole (10 μM). Mitochondrial membrane potential (ΔΨm) was measured using JC-1 staining (fluorescent probe), and cytochrome c release from mitochondria was analyzed by western blot [5]
The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms[3].

In rat models of ischemic stroke: Male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 hours to induce ischemia. pramipexole was administered intravenously at a dose of 1 mg/kg immediately after reperfusion. Neurological function was evaluated using a standard scoring system at 24 hours post-surgery, and infarct volume was measured by TTC staining of brain sections [5]
A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson's disease and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemia/reperfusion injury[5].

pramipexole is rapidly absorbed after oral administration, with a time to peak plasma concentration (Tmax) of approximately 6 hours. Oral bioavailability is about 90%, and plasma protein binding is low (<20%). It has an elimination half-life of 8-12 hours and is primarily excreted unchanged in urine [1]
- pramipexole exhibits 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 the organic cation transporter 3 (OCT3) [2]

- pramipexole showed low acute toxicity in animal studies, with a median lethal dose (LD50) >2000 mg/kg following oral administration in mice. Repeated dose studies in rats and dogs did not reveal significant hepatic or renal toxicity [1]
- pramipexole has minimal potential for drug-drug interactions due to its low plasma protein binding and limited metabolism by cytochrome P450 enzymes [1]
- In mesencephalic cultures, pramipexole (1 μM) reduced levodopa-induced toxicity, as indicated by decreased ROS production, caspase-3 activation, and apoptotic cell death [4]
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of pramipexole during breastfeeding, but it suppresses serum prolactin and may interfere with breastfeeding. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. Pramipexole lowers serum prolactin.[1] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

[1]. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther, 2006. 28(8): p. 1065-78.

[2]. Blood-brain barrier transport of pramipexole, a dopamine D2 agonist. Life Sci. 2007 Apr 3;80(17):1564-71.

[3]. Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling. Neural Plast. 2018; 2018: 4196961.

[4]. Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole. J Neural Transm (Vienna). 1997;104(2-3):209-28.

[5]. Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke. Dis Model Mech. 2019 Aug 1; 12(8): dmm033860.

- pramipexole is a non-ergoline dopamine agonist that selectively binds to D2, D3, and D4 receptors, with highest affinity for D3 receptors [1]
- The neuroprotective effects of pramipexole in various models (dopaminergic neurons, ischemic stroke) are linked to multiple mechanisms, including activation of BDNF/mTOR signaling (structural plasticity) and inhibition of mitochondrial dysfunction (reduced mPTP opening, cytochrome c release) [3,5]
- pramipexole is clinically used for treating Parkinson's disease, leveraging its dopamine receptor agonist activity to modulate dopaminergic neurotransmission [1]

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Pramipexole hydrochloride anhydrous is a hydrochloride that is the anhydrous dihydrochloride salt of pramipexole. It has a role as a dopamine agonist and an antiparkinson drug. It contains a pramipexole(2+).
Pramipexole Dihydrochloride is the hydrochloride salt of pramipexole, a benzothiazole derivative. As a nonergot dopamine agonist, pramipexole binds to D2 and D3 dopamine receptors in the striatum and substantia nigra of the brain. Compared to other dopamine agonists, the use of this agent may be associated with fewer dyskinetic side effects in treated subjects. (NCI04)
A benzothiazole derivative and dopamine agonist with antioxidant properties that is used in the treatment of PARKINSON DISEASE and RESTLESS LEGS SYNDROME.
See also: Pramipexole (has active moiety).

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Drug Indication
Sifrol is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i. e. over the course of the disease, though to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end-of-dose or 'on-off' fluctuations). Sifrol is indicated for symptomatic treatment of moderate to severe idiopathic restless-legs syndrome in dosages up to 0. 54 mg of base (0. 75 mg of salt).

C10H19CL2N3S

284.25

283.067

C, 42.25; H, 6.74; Cl, 24.95; N, 14.78; S, 11.28

104632-25-9

Dexpramipexole dihydrochloride; 104632-27-1; Pramipexole; 104632-26-0; Pramipexole dihydrochloride hydrate; 191217-81-9; Dexpramipexole; 104632-28-2; Pramipexole-d7 dihydrochloride; Pramipexole-d5 dihydrochloride; 1217601-58-5; Pramipexole-d7-1 dihydrochloride; 2702798-58-9

119569

White to off-white solid powder

378ºC at 760 mmHg

288-290ºC

182.4ºC

6.49E-06mmHg at 25°C

4.158

4

4

3

16

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]

QMNWXHSYPXQFSK-KLXURFKVSA-N

InChI=1S/C10H17N3S.2ClH/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/t7-;;/m0../s1

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

Pramipexole 2HCl; Pramipexole Dihydrochloride; Mirapex ER; Pramipexole hydrochloride; Pramipexole dihydrochloride; 104632-25-9; (S)-N6-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride; Mirapex ER; PRAMIPEXOLE HYDROCHLORIDE; (S)-Pramipexole Dihydrochloride; PRAMIPEXOLE HCl; Pramipexole (dihydrochloride); SND919; Mirapex; SUD 919CL2Y; SUD919CL2Y; U-98528E; Sifrol; SND 919; KNS-760704

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)

DMSO: ~56 mg/mL (~197.0 mM)

Solubility in Formulation 1: 100 mg/mL (351.80 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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