Radiprodil
(Synonyms: RGH-896) 目录号 : GC34753
An NMDA receptor antagonist
Cas No.:496054-87-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Radiprodil is an antagonist of NR2B subunit-containing NMDA receptors (IC50 = 8 nM).1 It is selective for NR2B subunit-containing NMDA receptors over NR1 and NR2A subunit-containing NMDA receptors at 15 ?M. Radiprodil (10 nM) reduces amyloid β (1-42) (Aβ42) and Aβ40-induced decreases in dendritic spine density in mouse hippocampal CA1 pyramidal neurons.2 Radiprodil (2 mg/kg) restores novel object-stimulated locomotion in a marmoset model of MPTP-induced Parkinson's disease.3
1.Barta-Szalai, G., Borza, I., Bozó, E., et al.Oxamides as novel NR2B selective NMDA receptor antagonistsBioorg. Med. Chem. Lett.14(15)3953-3956(2004) 2.Rammes, G., Seeser, F., Mattusch, K., et al.The NMDA receptor antagonist radiprodil reverses the synaptotoxic effects of different amyloid-beta (Ab) species on long-term potentiation (LTP)Neuropharmacology140(10)184-192(2018) 3.Michel, A., Nicolas, J.M., Rose, S., et al.Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosetsPLoS One12(8)e0182887(2017)
| Cas No. | 496054-87-6 | SDF | |
| 别名 | RGH-896 | ||
| Canonical SMILES | O=C(NC1=CC=C2NC(OC2=C1)=O)C(N3CCC(CC4=CC=C(F)C=C4)CC3)=O | ||
| 分子式 | C21H20FN3O4 | 分子量 | 397.4 |
| 溶解度 | DMSO : 250 mg/mL (629.09 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5164 mL | 12.5818 mL | 25.1636 mL |
| 5 mM | 0.5033 mL | 2.5164 mL | 5.0327 mL |
| 10 mM | 0.2516 mL | 1.2582 mL | 2.5164 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome
Ann Clin Transl Neurol 2020 Mar;7(3):343-352.PMID:32106360DOI:10.1002/acn3.50998.
Objective: Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test Radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS. Methods: Radiprodil has been tested in three models, including pentylenetetrazole-induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study. Results: Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of Radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm-free and two showed clinical improvement without reaching spasm-freedom. After Radiprodil withdrawal, the one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs. Interpretation: Radiprodil showed prominent anti-seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that Radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.
A pharmacokinetic study of Radiprodil oral suspension in healthy adults comparing conventional venous blood sampling with two microsampling techniques
Pharmacol Res Perspect 2019 Jan 28;7(1):e00459.PMID:30705758DOI:10.1002/prp2.459.
In this phase I, single-center, open-label study of ten heathy adults (18-45 years; NCT02647697), the PK, safety, and tolerability profile of Radiprodil oral suspension in healthy adults were assessed, as well as two PK microsampling techniques. All participants received a single 30 mg Radiprodil dose (12 mL oral suspension). Blood was collected at various time points using conventional venous sampling (intravenous catheter or venepuncture), and Mitra™ and Aqua-Cap™ Drummond microsampling (finger-prick and blood taken from venous blood sample tubes). Geometric mean Radiprodil plasma concentrations from conventional venous samples were above the lower limit of quantification up to 48 hours after administration of a single oral dose of Radiprodil. Geometric mean AUC inf and Cmax were 2042 h ng mL -1 and 89.4 ng mL -1, respectively. Geometric mean t½ was 15.8 hour; median tmax was 4 hour (range: 3-6 hour). Radiprodil exposure variables for Aqua-Cap™ Drummond sampling were similar to the conventional venous-derived data. Conversely, Radiprodil exposure variables were lower with Mitra™ sampling compared with conventional venous sampling. The geometric mean ratio (90% confidence interval) for Cmax of conventional venous versus Mitra™ and Aqua-Cap™ Drummond sampling (finger-prick blood) was 0.89 (0.85, 0.94) and 1.03 (0.97,1.08), respectively, and therefore within the conventional bioequivalence range (0.80-1.25). Radiprodil oral suspension had an acceptable safety, tolerability, and palatability profile. The PK profile of Radiprodil oral suspension was established in healthy adults, and was comparable when analyzed using conventional versus microsampling techniques. These results will support future Radiprodil paediatric studies.
Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets
PLoS One 2017 Aug 30;12(8):e0182887.PMID:28854243DOI:10.1371/journal.pone.0182887.
Objective: Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). Background: In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. Methods: Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD. Results: When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects. Conclusion: We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.
The NMDA receptor antagonist Radiprodil reverses the synaptotoxic effects of different amyloid-beta (Aβ) species on long-term potentiation (LTP)
Neuropharmacology 2018 Sep 15;140:184-192.PMID:30016667DOI:10.1016/j.neuropharm.2018.07.021.
Aβ1-42 is well accepted to be a primary early pathogenic agent in Alzheimer's disease (AD). However, other amyloid peptides are now gaining considerable attention as potential key participants in AD due to their proposed higher neuronal toxicity. Impairment of the glutamatergic system is also widely accepted to be associated with pathomechanisms underlying AD. There is ample evidence that Aβ1-42 affects GLUN2B subunit containing N-methyl-D-aspartate receptor function and abolishes the induction of long term potentiation (LTP). In this study we show that different β-amyloid species, 1-42 Aβ1-42 and 1-40 (Aβ1-40) as well as post-translationally modified forms such as pyroglutamate-modified amyloid-(AβpE3) and nitrated Aβ (3NTyr10-Aβ), when applied for 90 min to murine hippocampal slices, concentration-dependently prevented the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with IC50s of 2, 9, 2 and 35 nM, respectively whilst having no effect on baseline AMPA receptor mediated fEPSPs. Aβ1-43 had no effect. Interestingly, the combination of all Aβ species did not result in any synergistic or additive inhibitory effect on LTP - the calculated pooled Aβ species IC50 was 20 nM. A low concentration (10 nM) of the GLUN2B receptor antagonist Radiprodil restored LTP in the presence of Aβ1-42, 3NTyr10-Aβ, Aβ1-40, but not AβpE3. In contrast to AMPA receptor mediated fEPSPs, all different β-amyloid species tested at 50 nM supressed baseline NMDA-EPSC amplitudes. Similarly, all different Aβ species tested decreased spine density. As with LTP, Radiprodil (10 nM) reversed the synaptic toxicity of Aβ species but not that of AβpE3. These data do not support the enhanced toxic actions reported for some Aβ species such as AβpE3, nor synergistic toxicity of the combination of different Aβ species. However, whilst in our hands AβpE3-42 was actually less toxic than Aβ1-42, its effects were not reversed by Radiprodil indicating that the target receptors/subunits mediating such synaptotoxicity may differ between the different Aβ species tested.
GRIN2B gain of function mutations are sensitive to Radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors
Neuropharmacology 2017 Sep 1;123:322-331.PMID:28533163DOI:10.1016/j.neuropharm.2017.05.017.
De novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of Radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg2+ was completely abolished in N615I and V618G variants. In fact, Mg2+ enhanced glutamate responses in those variants. The potency of Radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg2+ insensitive variants, Radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg2+. The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor Radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that Radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations.