Pardoprunox hydrochloride (SLV-308 hydrochloride)
(Synonyms: 盐酸帕多芦诺,SLV-308 hydrochloride; DU-126891 hydrochloride) 目录号 : GC30980A dopamine D2 and D3 receptor partial agonist and 5-HT1A agonist
Cas No.:269718-83-4
Sample solution is provided at 25 µL, 10mM.
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Pardoprunox is a partial agonist of dopamine D2 and D3 receptors (EC50s = 10 and 0.63 nM, respectively) and a full agonist of the serotonin (5-HT) receptor subtype 5-HT1A (EC50 = 501 nM) in radioligand binding assays.1 It is selective for dopamine D2 and D3 and 5-HT1A receptors over a panel of neurotransmitter receptors (Kis = >1,000 nM). Pardoprunox reduces the accumulation of cAMP induced by forskolin in a concentration-dependent manner and blocks quinpirole-induced inhibition of dopamine release (pA2 = 8.5) in rat striatal slices. Pardoprunox increases contralateral turning behavior in a 6-OHDA rat model of Parkinson’s disease (ED50 = 0.03 mg/kg).2 It also reduces hyperlocomotion induced by amphetamine and induces 5-HT1A-mediated flat body posturing and lower lip retraction in rats. Pardoprunox (0.01-0.3 mg/kg) increases locomotor activity in a marmoset model of Parkinson’s disease induced by MPTP in a dose-dependent manner. Formulations containing pardoprunox are under clinical investigation for the treatment of Parkinson’s disease-associated motor fluctuations.3
1.Glennon, J.C., Van Scharrenburg, G., Ronken, E., et al.In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): A novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonistSynapse60(8)599-608(2006) 2.Jones, C.A., Johnston, L.C., Jackson, M.J., et al.An in vivo pharmacological evaluation of pardoprunox (SLV308)—A novel combined dopamine D2/D3 receptor partial agonist and 5-HT1A receptor agonist with efficacy in experimental models of Parkinson's diseaseEur. Neuropsychopharmacol.20(8)582-593(2010) 3.Rascol, O., Brozova, J., Hauser, R.A., et al.Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: Results of a double-blind, randomized, placebo-controlled, trialParkinsonism Relat. Disord.18(4)370-376(2012)
Cas No. | 269718-83-4 | SDF | |
别名 | 盐酸帕多芦诺,SLV-308 hydrochloride; DU-126891 hydrochloride | ||
Canonical SMILES | O=C1OC2=C(N3CCN(C)CC3)C=CC=C2N1.[H]Cl | ||
分子式 | C12H16ClN3O2 | 分子量 | 269.73 |
溶解度 | DMF: 1 mg/ml,DMSO: 5 mg/ml,Ethanol: 0.1 mg/ml,PBS (pH 7.2): 5 mg/ml | 储存条件 | Store at -20°C |
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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 |
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The partial dopamine agonist pardoprunox (SLV308) administered in combination with l-dopa improves efficacy and decreases dyskinesia in MPTP treated common marmosets
Dopamine agonist treatment in early Parkinson's disease (PD) induces less dyskinesia than l-dopa. However, once dyskinesia has developed, dopamine agonists administered with l-dopa exacerbate involuntary movements. The dopamine partial D2/D3 agonist pardoprunox reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates without hyperactivity, indicating that pardoprunox may alleviate dyskinesia without compromising l-dopa's beneficial actions. This study examines a clinical scenario in which pardoprunox was introduced, in an l-dopa sparing strategy, to existing l-dopa treatment in MPTP-treated marmosets previously primed to express dyskinesia. l-Dopa (5-10 mg/kg) produced effects, which were stable over the 13 treatment days, of increased locomotor activity, reversed motor disability and marked dyskinesia. Pardoprunox (SLV308; 0.0125-0.025 mg/kg) plus l-dopa (3-10 mg/kg) administration increased locomotor activity over the same treatment period and initially produced an equivalent reversal of motor disability compared to l-dopa, however this effect was enhanced as treatment progressed. This reflected the prolonged duration of effect of pardoprunox compared to that of l-dopa. While pardoprunox plus l-dopa treatment initially produced dyskinesia to the same extent as l-dopa alone, the intensity diminished as treatment progressed and it was significantly different at the end of the study. On subsequent l-dopa challenge there was no difference in motor disability reversal between those animals previously treated with pardoprunox plus l-dopa compared to l-dopa alone but the combination treatment produced significantly less dyskinesia. These data suggest that pardoprunox may provide therapeutic benefit in mid to late stage PD by reducing dyskinesia while maintaining efficacy when used with concomitant l-dopa treatment.