Pramipexole 2HCl Monohydrate 191217-81-9_Dopamine Receptor_GPCR & G Protein_Signaling Pathways_Products

Pramipexole 2HCl monohydrate (formerly known as SND 919; (S)-Pramipexole; trade name Mirapex among others) is the dihydrochloride salt and hydrated form of of pramipexole which is a potent agonist of the Gαi-linked dopamine receptors D2, D3, and D4 with neuroprotective effects. Pramipexole is an innovative chemical dopamine agonist that is used to treat Parkinson's disease symptoms. It also has antioxidant properties and protects substantia nigral dopamine neurons in hypoxic-ischemic and methamphetamine models. 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.

Physicochemical Properties

Molecular Formula

C10H21CL2N3OS

Molecular Weight

302.26

Exact Mass

301.078

Elemental Analysis

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

CAS #

191217-81-9

Related CAS #

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

PubChem CID

166589

Appearance

White to off-white solid powder

Boiling Point

378ºC at 760 mmHg

Melting Point

290 °C(dec.)

Flash Point

182.4ºC

Vapour Pressure

9.93E-11mmHg at 25°C

LogP

4.094

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

188

Defined Atom Stereocenter Count

SMILES

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]

InChi Key

APVQOOKHDZVJEX-QTPLPEIMSA-N

InChi Code

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

Chemical Name

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

Synonyms

SND 919; Pramipexole dihydrochloride monohydrate; 191217-81-9; Mirapex; (S)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride hydrate; PRAMIPEXOLE HYDROCHLORIDE; Sifrol; Daquiran; Pramipexole hydrochloride hydrate; Pramipexole Dihydrochloride Monohydrate; Pramipexole Dihydrochloride; SND-919; SND919;Pramipexole 2HCl Monohydrate; Pramipexole 2HCl H2O

HS Tariff Code

2934.99.9001

Storage

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.

Shipping Condition

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

Biological Activity

Targets

D₂ Receptor ( Ki = 3.9 nM ); D₃ Receptor ( Ki = 0.5 nM ); D₄ Receptor ( Ki = 1.3 nM )

ln Vitro

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.

ln Vivo

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%.

Cell Assay

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].

Animal Protocol

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]

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

Mice

Toxicity/Toxicokinetics

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.

References

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

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

Additional Infomation

Pramipexole hydrochloride is a hydrate that is the monohydrate of the dihydrochloride salt of pramiprexole. It has a role as a dopamine agonist and an antiparkinson drug. It contains a member of pramipexole hydrochloride anhydrous and a pramipexole(2+).
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 (annotation moved to); Pramipexole Dihydrochloride (annotation moved to).

Drug Indication
Pramipexole Accord is indicated in adults 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, through 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).
DAQUIRAN tablets are indicated for treatment of the signs and symptoms of advanced idiopathic Parkinson's disease in combination with levodopa, i. e. over the course of the disease, when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or " on off" fluctuations).
Combined vocal and multiple motor tic disorder (de la Tourette), Restless Legs Syndrome
Combined vocal and multiple motor tic disorder (de la Tourette), Restless Legs Syndrome

Solubility Data

Solubility (In Vitro)

DMSO: ~41 mg/mL (~135.6 mM)

Water: ~60 mg/mL (~198.5 mM)

Ethanol: <1 mg/mL

Solubility (In Vivo)

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.

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.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.3084 mL	16.5420 mL	33.0841 mL
	5 mM	0.6617 mL	3.3084 mL	6.6168 mL
	10 mM	0.3308 mL	1.6542 mL	3.3084 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

Pramipexole 2HCl Monohydrate 191217-81-9

CAS No.: 191217-81-9

Physicochemical Properties

Biological Activity

Solubility Data