Radiprodil (RGH-896)   中文名称: 雷拉地尔

NMDA NR2B

在 Aβ1-42、3NTyr10-Aβ 和 Aβ1-40 存在的情况下，用 Radiprodil (10 nM) 预孵育可以恢复长时程增强 (LTP)，但在 AβpE3 存在的情况下则不能恢复长时程增强 (LTP) [2]。 Radiodil (10 nM) 可逆转 3NTyr-AβAβ1-40 和 Aβ1-42 对 LTP 的突触毒性，但不能逆转 AβpE3-42[2]。

在 Mg2+ 不敏感版本中，radiprodil 抑制 NMDA 电流的强度类似于没有 Mg2+ 时所达到的强度 [3]。 Radiprodil 在 pH 7.0 时的有效性高于 pH 7.6 时的有效性，这表明即使在酸性环境（如长时间癫痫性抽搐中所见的环境）中，Radiprodil 也可能能够阻断谷氨酸诱导的 NMDA 电流 [3]。

Aβ1-42被广泛认为是阿尔茨海默病（AD）的主要早期致病因子。然而，由于其他淀粉样肽具有较高的神经元毒性，它们现在作为阿尔茨海默病的潜在关键参与者受到了相当大的关注。谷氨酸能系统的损伤也被广泛认为与阿尔茨海默病的病理机制有关。有充分证据表明，Aβ1-42会影响含有N-甲基-D-天冬氨酸受体的GLUN2B亚基的功能，并消除长期增强（LTP）的诱导。在这项研究中，我们发现，当将不同的β-淀粉样蛋白物种1-42 Aβ1-42和1-40（Aβ1-40）以及翻译后修饰的形式，如焦谷氨酸修饰的淀粉样蛋白（AβpE3）和硝化的Aβ（3NTyr10-Aβ）应用于小鼠海马切片90分钟时，浓度依赖性地阻止了Schaffer侧支强直刺激后CA1-LTP的发展，IC50分别为2、9、2和35 nM，而对基线AMPA受体介导的fEPSP没有影响。Aβ1-43没有影响。有趣的是，所有Aβ物种的组合对LTP没有产生任何协同或相加的抑制作用——计算出的合并Aβ物种IC50为20 nM。低浓度（10 nM）的GLUN2B受体拮抗剂Radiprodil在Aβ1-42、3NTyr10-Aβ、Aβ1-40存在的情况下恢复了LTP，但AβpE3不存在。与AMPA受体介导的fEPSP相反，在50 nM下测试的所有不同的β-淀粉样蛋白物种都抑制了基线NMDA-EPSC振幅。同样，所有不同的Aβ物种都降低了脊柱密度。与LTP一样，Radiprodil（10 nM）逆转了Aβ物种的突触毒性，但没有逆转AβpE3的突触毒性。这些数据不支持某些Aβ物种（如AβpE3）报告的增强毒性作用，也不支持不同Aβ物种组合的协同毒性。然而，虽然在我们手中，AβpE3-42的毒性实际上比Aβ1-42小，但Radiprodil并没有逆转其作用，这表明介导这种突触毒性的靶受体/亚基在所测试的不同Aβ物种之间可能不同[2]。

GRIN1/GRIN2B human mRNA was injected with an automated micro-injector using a glass micropipette (5.5 μm diameter, MCS) into the cytoplasm of Xenopus oocytes (stage V–VI) previously dissected and de-folliculated. Oocytes were microinjected with ∼25 nl of mRNA dissolved in RNAse free water (Ambion, Thermo Fisher Scientific, Waltham, MA). Receptors were allowed to express for 3–6 days at 17 °C in a Barth's solution containing (in mM): NaCl (88), KCl (1), NaHCO3 (2.4), Ca(NO3)2 (0.33), CaCl2 (0.41), MgSO4 (0.82), Tris-HCl (5) pH 7.4 and supplemented with penicillin/streptomycin (100 IU/mL). Oocytes were washed every day with Barth's solution containing antibiotics.[3]

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For expression of GluN1/GluN2B receptors, the solution contained the transcripts coding for the different subunits at a concentration of 0.01 ng/nl. For the dose-response for glutamate experiments, all oocytes were injected with the same quantity of GRIN1/GRIN2B mRNAs (ratio 1:5, 0.25 ng total). However, GluN1/GluN2B (N615I) and GluN1/GluN2B (V618G) variants displayed currents that were smaller than those elicited in GluN1/GluN2B (WT) and in GluN1/GluN2B R540H. Therefore, for subsequent experiments, the mRNA quantity was adjusted (2.5 ng total; 0.1 ng/nl solution, total volume ± 25 nl) for GluN1/GluN2B (N615I) and GluN1/GluN2B (V618G) variants in order to obtain suitable currents.[3]

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Radiprodil was administered as a solution at a dose volume of 2 mL/kg by oral gavage.The vehicle was composed of 0.1% (w/v) Tween 80, 0.1% (w/v) silicone antifoam 1510 US, 20% (w/v) Kleptose HPB, 1.0% (w/v) methylcellulose in water. Before initiating the Radiprodil & Tozadenant combination experiment, 14 primates were challenged with a dose of 8 mg/kg (po) of L-Dopa and behaviour was recorded for 5 hours. This “Pre-L-Dopa-test” was used to select the 12 subjects required for the study. Their response to the L-Dopa challenge was subsequently used as a comparator to the ensuing response to the different drug treatments and combinations. The effects of the drugs alone or in combination were assessed after acute oral gavage.[4]
This experiment investigated the effects on motor deficits of Radiprodil plus Tozadenant twice daily at an interval of 5 hrs according to a modified Latin square design in n = 12 MPTP-treated marmosets (S1 Table). At the time of the second drugs administration a novel object (cotton reel, table tennis ball) was placed into the cage. The four different treatments were (1) Tozadenant (150 mg/kg) plus Radiprodil (2.0 mg/kg), (2) Tozadenant (150 mg/kg) plus vehicle, (3) Radiprodil (2.0 mg/kg) plus vehicle, (4) vehicle.[4]

[1]. Mony L, et al. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol. 2009 Aug;157(8):1301-17.
[2]. Rammes G, et al. 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.
[3]. Mullier B, et al. 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.
[4]. Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets. PLoS One. 2017; 12(8): e0182887.

Radiprodil has been used in trials studying the treatment of Infantile Spasms (IS) and Diabetic Peripheral Neuropathic Pain.

C21H20FN3O4

397.4064

397.144

C, 63.47; H, 5.07; F, 4.78; N, 10.57; O, 16.10

496054-87-6

496054-87-6; 1204354-40-4 (dihydrate)

10200813

Typically exists as Light yellow to yellow solids at room temperature

3.103

95.67

2

5

3

29

629

0

GKGRZLGAQZPEHO-UHFFFAOYSA-N

InChI=1S/C21H20FN3O4/c22-15-3-1-13(2-4-15)11-14-7-9-25(10-8-14)20(27)19(26)23-16-5-6-17-18(12-16)29-21(28)24-17/h1-6,12,14H,7-11H2,(H,23,26)(H,24,28)

2-(4-((4-Fluorophenyl)methyl)piperidin-1-yl)-2-oxo-N-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)acetamide

RGH-896; RGH896; RGH 896; Radiprodil; Radiprodil [INN]; 5XGC17ZKUF; CHEMBL182066; 2-(4-(4-Fluorobenzyl)piperidin-1-yl)-2-oxo-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetamide; 2-(4-((4-Fluorophenyl)methyl)piperidin-1-yl)-2-oxo-N-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)acetamide;

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)

DMSO : ~250 mg/mL (~629.09 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.23 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (5.23 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.23 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。