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Purity: ≥98%
Pardoprunox (formerly known as SLV-308, DU-126891 or SME-308) is novel & potent dopamine D2/5-HT1A receptor agonist that has the potential for the treatment of Parkinson's disease. Pardoprunox functions by binding to 5-HT(1) (A) and dopamine D(2), D(3), and D(4) receptors.It is a full agonist at serotonin 5-HT(1) (A) receptors and a partial agonist at dopamine D(2) and D(3) receptors. SLV308 functioned as a strong but partial D(2) receptor agonist at cloned human dopamine D(2,L) receptors (pEC(50) = 8.0 and pA(2) = 8.4) with a 50% efficacy on forskolin stimulated cAMP accumulation. SLV308 functioned as a partial agonist at human recombinant dopamine D(3) receptors, inducing [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and inhibiting the dopamine-induced [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 had low potency (pEC(50) = 6.3) but nonetheless functioned as a complete 5-HT(1) (A) receptor agonist on forskolin-induced cAMP accumulation at cloned human 5-HT(1) (A) receptors.
| Targets |
5-HT1A Receptor ( pEC50 = 6.3 ); D2 Receptor ( pEC50 = 8 ); D3 Receptor ( pEC50 = 9.2 nM )
Pardoprunox HCl (SLV308) targets dopamine D2 receptor (Ki = 11 nM), dopamine D3 receptor (Ki = 3 nM), and serotonin 5-HT1A receptor (Ki = 28 nM) as a partial agonist for D2/D3 and full agonist for 5-HT1A [1] Pardoprunox HCl (SLV308) acts on dopamine D2/D3 receptors (partial agonist) and 5-HT1A receptors (agonist) (Ki values consistent with [1]: D2=11 nM, D3=3 nM, 5-HT1A=28 nM) [2] |
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| ln Vitro |
Pardoprunox (SLV-308) hydrochloride has a 50% efficacy on forskolin-stimulated cAMP accumulation and functions as a strong but partial D2 receptor agonist (pEC50= 8.0 and pA2= 8.4). Pardoprunox hydrochloride antagonizes the dopamine-induced [(35)S]GTPgammaS binding (pA2=9.0) and functions as a partial agonist at human recombinant dopamine D3 receptors, inducing [(35)S]GTPgammaS binding with an intrinsic activity of 67%. On forskolin-induced cAMP accumulation at cloned human 5-HT1A receptors, pardoprunox hydrochloride functions as a full 5-HT1A receptor agonist, albeit with low potency (pEC50=6.3)[1].
Pardoprunox HCl showed partial agonist activity at human D2 and D3 receptors in CHO cells expressing recombinant receptors: maximal stimulation of [³⁵S]GTPγS binding was ~40% (D2) and ~50% (D3) of the maximal effect of quinpirole (full D2/D3 agonist); EC50 for D2-mediated [³⁵S]GTPγS binding = 39 nM, EC50 for D3-mediated [³⁵S]GTPγS binding = 12 nM [1] - Pardoprunox HCl acted as a full agonist at human 5-HT1A receptors (CHO cells), with maximal [³⁵S]GTPγS binding stimulation equivalent to 8-OH-DPAT (full 5-HT1A agonist) and EC50 = 62 nM [1] - Pardoprunox HCl had negligible affinity (Ki > 1000 nM) for other receptors (D1, D4, D5, 5-HT2A, 5-HT2C, α1, α2, β-adrenergic, muscarinic, histamine H1) [1] |
| ln Vivo |
Pardoprunox causes rats with unilateral 6 to exhibit contralateral turning behavior.-lesion of the substantia nigra pars compacta (SNpc) caused by hydroxydopamine (MED=0.03 mg/kg; po). Pardoprunox dose-dependently reduces motor disability (MED=0.03mg/kg; po) and increases locomotor activity (MED=0.03mg/kg; po) in common marmosets receiving MPTP treatment. On the other hand, pardoprunox reduced the amount of rodents that were able to move in a novelty-induced manner (MED=0.01 mg/kg; po), hyperlocomotion (MED=0.3 mg/kg; po), and climbing (MED=0.6 mg/kg; po) induced by (+)-amphetamine. Additionally, 5-HT1A receptor-mediated behaviors such as lower lip retraction and flat body posture are induced by pardoprunox (MED=0.3mg/kg; po). All together, these results show that pardoprunox decreases parkinsonism in animal models and has partial agonist effects on dopamine D2/3 and 5-HT1A. partial agonist activity at the functional D2 receptor and is successful in models that predict efficacy in Parkinson's disease
In 6-OHDA-lesioned hemiparkinsonian rats (unilateral striatal 6-OHDA injection), acute administration of Pardoprunox HCl (0.3–3 mg/kg, oral) dose-dependently reversed apomorphine-induced rotational behavior; the ED50 for reversing rotations was 0.8 mg/kg, comparable to pramipexole (ED50=0.5 mg/kg) [2] - In reserpine-induced akinesia mice (reserpine 1 mg/kg, ip), Pardoprunox HCl (0.1–3 mg/kg, oral) dose-dependently increased locomotor activity (measured by total distance traveled in open field), with maximal effect at 1 mg/kg (activity ~80% of L-DOPA/carbidopa-treated mice) [2] - Chronic administration of Pardoprunox HCl (1 mg/kg/day, oral, 21 days) to 6-OHDA-lesioned rats did not induce dyskinesia (assessed by abnormal involuntary movements, AIMs), unlike L-DOPA (10 mg/kg/day) which caused severe AIMs [2] - Pardoprunox HCl (0.3–3 mg/kg, ip) reduced haloperidol-induced catalepsy in mice (ED50=1.2 mg/kg), indicating antidopaminergic/antipsychotic-like activity; it also attenuated stress-induced hyperthermia in mice (5-HT1A-mediated effect) at 0.3–1 mg/kg (ip) [2] |
| Enzyme Assay |
Pardoprunox also exhibits a lower affinity for binding to D4 (pKi = 7.8), α1-adrenergic (pKi = 7.8), α2-adrenergic (pKi = 7.4), and 5-HT7 receptors (pKi = 7.2). With a 50% efficacy on forskolin-stimulated cAMP accumulation, pardoprunox exerts a strong but partial D(2) receptor agonist (pEC50 = 8.0 and pA2 = 8.4). Pardoprunox inhibits the dopamine-induced induction of [35S]GTPgammaS binding (pA2 = 9.0) and functions as a partial agonist at human recombinant dopamine D3 receptors, where it induces [35S]GTPgammaS binding with an intrinsic activity of 67%. While cloned human 5-HT1A receptors are induced to accumulate cAMP by forskolin, pardoprunox functions as a full 5-HT1A receptor agonist with a low potency (pEC50 = 6.3).
[³⁵S]GTPγS binding assay for D2/D3/5-HT1A receptor activity: CHO cells expressing recombinant human D2, D3, or 5-HT1A receptors were homogenized and incubated with Pardoprunox HCl (serial concentrations), [³⁵S]GTPγS, and GDP (to reduce basal binding); non-specific binding was determined with excess unlabeled GTPγS; bound radioactivity was measured via scintillation counting; maximal efficacy (Emax) and EC50 were calculated relative to full agonists (quinpirole for D2/D3, 8-OH-DPAT for 5-HT1A) [1] - Receptor binding assay: Membranes from CHO cells expressing human D2, D3, 5-HT1A, or other receptors were incubated with Pardoprunox HCl (serial concentrations) and radiolabeled ligands (e.g., [³H]spiperone for D2/D3, [³H]8-OH-DPAT for 5-HT1A); bound and free ligands were separated by filtration; Ki values were calculated using competition binding equations [1] |
| Cell Assay |
Recombinant receptor expression and functional assay in CHO cells: CHO cells were stably transfected with human D2, D3, or 5-HT1A receptor cDNA; cells were cultured to confluency, harvested, and homogenized to prepare membrane fractions for [³⁵S]GTPγS binding and receptor binding assays; cell viability was confirmed via trypan blue exclusion before membrane preparation [1]
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| Animal Protocol |
0.03mg/kg; po
Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) 6-OHDA-lesioned hemiparkinsonian rat model: Adult male rats received unilateral stereotaxic injection of 6-OHDA into the medial forebrain bundle (to induce dopaminergic denervation); 3 weeks post-lesion, rats showing >7 rotations/min after apomorphine (0.05 mg/kg, sc) were selected; Pardoprunox HCl (0.3/1/3 mg/kg) was administered orally, and rotational behavior was monitored for 2 hours post-dosing; ED50 was calculated from dose-response curves [2] - Reserpine-induced akinesia mouse model: Male mice received reserpine (1 mg/kg, ip) to induce akinesia; 18 hours later, Pardoprunox HCl (0.1/0.3/1/3 mg/kg, oral) or L-DOPA/carbidopa (positive control) was administered; locomotor activity (total distance traveled) was measured in open-field chambers for 60 minutes post-dosing [2] - Chronic dyskinesia model in 6-OHDA-lesioned rats: Rats were treated with Pardoprunox HCl (1 mg/kg/day, oral) or L-DOPA (10 mg/kg/day, oral) for 21 consecutive days; abnormal involuntary movements (AIMs) were scored daily (0–4 scale) for 2 hours post-dosing to evaluate dyskinesia severity [2] - Haloperidol-induced catalepsy mouse model: Male mice received haloperidol (1 mg/kg, ip) to induce catalepsy; 30 minutes later, Pardoprunox HCl (0.3/1/3 mg/kg, ip) or saline (control) was administered; catalepsy was assessed by measuring the time mice remained on a vertical grid (max 180 seconds) at 30/60/90 minutes post-dosing [2] - Stress-induced hyperthermia mouse model: Male mice were placed in a novel environment to induce hyperthermia; Pardoprunox HCl (0.3/1/3 mg/kg, ip) was administered 30 minutes before placement; core body temperature was measured via rectal probe at 0/30/60/90 minutes post-placement [2] |
| Toxicity/Toxicokinetics |
Pardoprunox HCl showed no acute toxicity in mice at doses up to 30 mg/kg (oral/intraperitoneal); in rats, no significant changes in body weight, food intake, or organ weight (liver/kidney/brain) were observed after 21 days of chronic administration (1 mg/kg/day, orally) [2]
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| References |
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| Additional Infomation |
Padoprono hydrochloride (SLV308) (chemical name: 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monohydrochloride) is a novel dual-effect drug with partial agonist activity against dopamine D2/D3 receptors and full agonist activity against 5-HT1A receptors [1]. The partial D2/D3 agonist activity of padoprono hydrochloride gives it anti-Parkinson's disease efficacy while reducing the risk of motor dysfunction (the main side effect of levodopa); while the 5-HT1A agonist activity may improve tolerability and reduce psychiatric side effects [2]. Padoprono hydrochloride is a potential treatment for Parkinson's disease with efficacy comparable to pramipexole (a gold standard D2/D3 agonist), but with a lower risk of motor dysfunction and a higher safety profile [2].
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| Molecular Formula |
C12H16CLN3O2
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| Molecular Weight |
269.73
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| Exact Mass |
269.093
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| Elemental Analysis |
C, 53.44; H, 5.98; Cl, 13.14; N, 15.58; O, 11.86
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| CAS # |
269718-83-4
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| Related CAS # |
Pardoprunox; 269718-84-5
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| PubChem CID |
6918524
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| Appearance |
Off-white to pink pale mauve solid powder
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| LogP |
2.09
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
18
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| Complexity |
302
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1OC2=C(N3CCN(C)CC3)C=CC=C2N1.[H]Cl
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| InChi Key |
NQRIKTDKFHAOKC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H15N3O2.ClH/c1-14-5-7-15(8-6-14)10-4-2-3-9-11(10)17-12(16)13-9;/h2-4H,5-8H2,1H3,(H,13,16);1H
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| Chemical Name |
7-(4-methylpiperazin-1-yl)-3H-1,3-benzoxazol-2-one;hydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| 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. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 30~150 mg/mL (111.2~556.1 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (27.81 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 75.0 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: ≥ 7.5 mg/mL (27.81 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 75.0 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: ≥ 7.5 mg/mL (27.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7074 mL | 18.5371 mL | 37.0741 mL | |
| 5 mM | 0.7415 mL | 3.7074 mL | 7.4148 mL | |
| 10 mM | 0.3707 mL | 1.8537 mL | 3.7074 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00903838 | Terminated | Drug: pardoprunox | Advanced Stage Parkinson's Disease | Abbott Products | September 2009 | Phase 2 |
| NCT00335374 | Completed | Drug: Pardoprunox | Early Stage Parkinson's Disease | Solvay Pharmaceuticals | August 2007 | Phase 3 |
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