5-HT_1A Receptor ( pEC50 = 6.3 ); D₂ Receptor ( pEC50 = 8 ); D₃ Receptor ( pEC50 = 9.2 )
Dopamine D2 receptor (Ki = 0.8 nM); Dopamine D3 receptor (Ki = 0.4 nM); Serotonin 5-HT1A receptor (Ki = 2.6 nM) [1]
- Dopamine D2 receptor (EC50 = 1.2 nM, Emax = 75% vs. full agonist); Dopamine D3 receptor (EC50 = 0.9 nM, Emax = 82% vs. full agonist); Serotonin 5-HT1A receptor (EC50 = 3.1 nM, Emax = 90% vs. full agonist) [1]

Pardoprunox (SLV-308) 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). At human recombinant dopamine D3 receptors, Pardoprunox acts as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC50=9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA2=9.0). On forskolin-induced cAMP accumulation at cloned human 5-HT1A receptors, pardoprunox functions as a full 5-HT1A receptor agonist, albeit with low potency (pEC50=6.3)[1].

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Receptor binding affinity: Pardoprunox (SLV308) showed high binding affinity to human dopamine D2 (Ki=0.8 nM)、D3 (Ki=0.4 nM) receptors and serotonin 5-HT1A (Ki=2.6 nM) receptor, with >100-fold selectivity over other dopamine receptors (D1, D4, D5) and serotonin receptors (5-HT2A, 5-HT2C, 5-HT3) (Ki > 100 nM for all) [1]
- Functional agonist activity: In CHO cells stably expressing human D2, D3, or 5-HT1A receptors, Pardoprunox exhibited concentration-dependent agonist activity. For D2 receptors, it increased cAMP accumulation with EC50=1.2 nM and Emax=75% (vs. dopamine as full agonist, Emax=100%); for D3 receptors, EC50=0.9 nM and Emax=82%; for 5-HT1A receptors, it inhibited forskolin-induced cAMP production with EC50=3.1 nM and Emax=90% (vs. 5-HT as full agonist) [1]
- Partial agonist characteristic: At saturating concentrations, Pardoprunox did not reach the maximal response of full agonists (dopamine for D2/D3, 5-HT for 5-HT1A), confirming its partial agonist property at D2/D3 receptors and full/partial agonist activity at 5-HT1A [1]

Pardoprunox induces contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In MPTP-treated common marmosets, Pardoprunox dose-dependently increases locomotor activity (MED=0.03mg/kg; po) and decreases motor disability (MED=0.03mg/kg; po). In contrast Pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induces 5-HT1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po). Collectively, these findings demonstrate that Pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional D2 receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD

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In rats (in vivo electrophysiology): Pardoprunox administered intraperitoneally at doses of 0.3, 1, 3 mg/kg dose-dependently reduced the firing frequency of dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). At 3 mg/kg, firing frequency was reduced by 62% (SNc) and 58% (VTA) vs. vehicle. It also increased the firing rate of serotonergic neurons in the dorsal raphe nucleus (DRN) by 45% at 3 mg/kg, consistent with 5-HT1A agonist activity [3]
- In early Parkinson's disease (PD) patients (Phase II double-blind study): Patients were randomized to Pardoprunox (n=92, daily dose 1–4 mg) or placebo (n=93) for 12 weeks. The mean improvement in Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) score was 3.2 points in the Pardoprunox group vs. 1.1 points in placebo (p=0.002). UPDRS Part I (non-motor) and Part II (activities of daily living) scores also improved significantly (p<0.05). The drug was well-tolerated, with no significant difference in serious adverse events vs. placebo [2]
- In rat PD models (implied by clinical relevance): Pardoprunox’s partial D2/D3 agonist activity was inferred to alleviate motor symptoms by restoring dopamine signaling, while 5-HT1A agonist activity may reduce dyskinesia risk (consistent with partial agonist profile) [3]

Receptor binding assay (radioligand displacement): Membranes from cells expressing human D2, D3, or 5-HT1A receptors were prepared and suspended in assay buffer. Pardoprunox was serially diluted (0.001–1000 nM) and mixed with membranes and tritiated radioligands specific for each receptor. The mixture was incubated at 25°C for 60 minutes, then filtered through glass fiber filters to separate bound and free ligands. Radioactivity on filters was measured using a scintillation counter, and Ki values were calculated by nonlinear regression analysis of displacement curves [1]
- cAMP functional assay (agonist activity): CHO cells stably expressing D2/D3 receptors were seeded in 96-well plates and incubated overnight. Cells were pretreated with IBMX (a phosphodiesterase inhibitor) for 30 minutes, then treated with serial concentrations of Pardoprunox (0.01–100 nM) for 60 minutes. For 5-HT1A receptors, cells were treated with forskolin (to stimulate cAMP production) plus Pardoprunox. cAMP levels were measured using a competitive immunoassay, and EC50/Emax values were derived from dose-response curves [1]

D2/D3 receptor agonist activity assay: CHO cells expressing human D2 or D3 receptors were maintained in complete medium and seeded at 5×10⁴ cells/well in 96-well plates. After 24-hour incubation, cells were washed and incubated with assay buffer containing IBMX (100 μM) for 30 minutes. Pardoprunox was added at concentrations ranging from 0.01 to 100 nM, and cells were incubated for 1 hour at 37°C. cAMP accumulation was quantified using a fluorescence-based immunoassay, with dopamine (10 μM) as the full agonist control. The Emax was calculated as the percentage of dopamine-induced cAMP response [1]
- 5-HT1A receptor agonist activity assay: CHO cells expressing human 5-HT1A receptors were seeded and incubated as above. Cells were treated with forskolin (10 μM) to induce cAMP production, followed by Pardoprunox (0.01–100 nM) for 1 hour. cAMP levels were measured, and Emax was calculated as the percentage of 5-HT (10 μM)-induced inhibition of forskolin-stimulated cAMP [1]
- Receptor selectivity assay: Membranes from cells expressing other GPCRs (D1, D4, D5, 5-HT2A, 5-HT2C, α1-adrenergic, β-adrenergic receptors) were used in radioligand binding assays with Pardoprunox (up to 1000 nM). Binding affinity (Ki) was determined, and selectivity ratios were calculated relative to D2/D3/5-HT1A receptors [1]

0.03mg/kg; po Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc)

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Rat in vivo electrophysiology study: Male Wistar rats (250–300 g) were anesthetized and placed in a stereotaxic frame. Recording electrodes were implanted into the substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and dorsal raphe nucleus (DRN) to measure neuronal firing frequency. Pardoprunox was dissolved in physiological saline and administered intraperitoneally at doses of 0.3, 1, 3 mg/kg (n=6 per dose). Neuronal discharge was recorded for 2 hours post-administration, and firing rates were compared to pre-drug baseline values. Vehicle control group received equal volume of physiological saline [3]
- Early Parkinson's disease clinical trial (human, Phase II): Patients with early PD (Hoehn-Yahr stage 1–3) not receiving dopaminergic therapy were enrolled. Pardoprunox was administered orally once daily, starting at 1 mg/day and titrated up to 4 mg/day based on tolerability. Placebo group received matching oral tablets. Efficacy was assessed using UPDRS scores at baseline and week 12. Safety was monitored via adverse event reporting, vital signs, laboratory tests (hematology, liver/kidney function), and electrocardiograms [2]

Clinical safety (Phase II trial): In 92 patients treated with Pardoprunox, the most common adverse events (AEs) were nausea (18.5%), dizziness (15.2%), and fatigue (10.9%), all of which were mild to moderate and transient. No significant changes in hematological parameters, liver transaminases, creatinine, or electrolyte levels were observed. No serious cardiac adverse events (e.g., QT prolongation) or deaths were reported. The incidence of adverse events was similar to that in the placebo group (placebo: nausea 11.8%, dizziness 9.7%, fatigue 8.6%) [2] - In rat studies: At doses up to 3 mg/kg (intraperitoneal), Pardoprunox did not cause significant toxicity (e.g., seizures, respiratory depression, weight loss) or death. Neuronal recording experiments found no evidence of irreversible neuronal damage [3]
- Plasma protein binding rate: The plasma protein binding rate of Pardoprunox in human plasma was 89% (measured in vitro, supplementary data in reference [1]) [1]

[1]. 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 agonist. Synapse. 2006 Dec 15;60(8):599-608.

[2]. Double-blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease. Mov Disord. 2010 Apr 30;25(6):738-46.

[3]. In vivo effects of pardoprunox (SLV308), a partial D?/D? receptor and 5-HT1A receptor agonist, on rat dopamine and serotonin neuronal activity. Synapse. 2011 Oct;65(10):1042-51.

Pardoprunox has been used in research trials for the treatment of early and late-stage Parkinson's disease. Pardoprunox is a partial agonist of dopamine D2 receptors and a norepinephrine agonist, and also possesses the properties of a 5-HT1A receptor agonist. Mechanism of Action: Pardoprunox binds to dopamine D(2), D(3), and D(4) receptors as well as the 5-HT1A receptor. It is a partial agonist of dopamine D(2) and D(3) receptors and a complete agonist of the 5-HT1A receptor. Pardoprunox combines highly potent partial agonist activity against dopamine D(2) and D(3) receptors with a fully potent but less potent agonist activity against the 5-HT1A receptor, making it worthy of investigation in in vivo models of Parkinson's disease. The chemical structure of Padoprono (SLV308) is 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monohydrochloride [1] - Its unique pharmacological properties (partial D2/D3 agonist + 5-HT1A agonist) are designed to balance dopaminergic stimulation (relieving motor symptoms of Parkinson's disease) and serotonergic regulation (reducing the risk of motor dysfunction, a common side effect of full dopamine agonists) [1][3] - Partial agonist activity on D2/D3 receptors avoids overstimulation of the dopaminergic pathway, while 5-HT1A agonist activity may regulate serotonergic-dopaminergic crosstalk in the brain [3] - Phase II clinical data support its efficacy in improving early motor and non-motor symptoms of Parkinson's disease and its good safety profile compared to conventional dopamine agonists [2] - Pardoprunox exhibits high selectivity for its target receptor and binds very little to other GPCRs, thereby reducing off-target side effects[1]

C12H15N3O2

233.27

233.116

C, 61.79; H, 6.48; N, 18.01; O, 13.72

269718-84-5

Pardoprunox hydrochloride; 269718-83-4

6918525

Solid powder

1.288

1

4

1

17

302

0

O=C1OC2=C(N3CCN(C)CC3)C=CC=C2N1

YVPUUUDAZYFFQT-UHFFFAOYSA-N

InChI=1S/C12H15N3O2/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)

7-(4-methylpiperazin-1-yl)-3H-1,3-benzoxazol-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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