| 规格 | 价格 | 库存 | 数量 |
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| 靶点 |
ML 297 has no effect whatsoever on GIRK2/3[1]. With an EC50 of 162 nM, ML297 exhibits concentration-dependent effectiveness in GIRK1/2-expressing cells [2]. It was demonstrated that ML297 is totally unable to alter the activity of HEK-293 cells that are only expressing GIRK2 and GIRKGIRK2/3 [2].
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| 体外研究 (In Vitro) |
ML 297 对 GIRK2/3[1] 没有任何影响。 ML297 的 EC50 为 162 nM，在表达 GIRK1/2 的细胞中表现出浓度依赖性的有效性 [2]。研究表明，ML297 完全无法改变仅表达 GIRK2 和 GIRKGIRK2/3 的 HEK-293 细胞的活性 [2]。
ML297 是通过高通量筛选及后续化学优化鉴定出的选择性GIRK1/2激活剂。其主要体外活性是通过铊离子流实验测定的对GIRK1/2通道的强效激活。 [1] 该化合物表现出良好的药物代谢和药代动力学特性，并且被描述为具有中枢渗透性。 [1] |
| 体内研究 (In Vivo) |
ML297（60 mg/kg；腹腔注射）在接受 PTZ 治疗时表现出显着的阻止癫痫发作和挽救生命的能力 [2]。
在小鼠的递增剂量研究中（10, 30, 60 mg/kg，腹腔注射），在所有测试剂量下，ML297未引起明显的痛苦迹象。 [2] 与溶剂对照组相比，给予ML297 (60 mg/kg，腹腔注射) 后，通过SmartCage系统测量，立即导致家庭笼内自主活动减少。 [2] 在同一剂量下（60 mg/kg，腹腔注射），ML297在转棒测试中仅引起轻微（14%）且无统计学意义的性能下降，表明其对运动的影响主要不是由于运动功能损伤。 [2] 在小鼠最大电休克（MES）癫痫发作模型中，ML297 (60 mg/kg，腹腔注射，测试前30分钟给药) 显著增加了癫痫发作的潜伏期，其效果与丙戊酸钠（150 mg/kg）相当。 [2] 在戊四唑（PTZ）诱导的癫痫发作模型中，与溶剂对照组相比，ML297 (60 mg/kg，腹腔注射，PTZ前30分钟给药) 显著降低了发生惊厥的小鼠百分比，并显著提高了存活率。 [2] |
| 细胞实验 |
用于表征ML297 及其类似物的主要基于细胞的实验是铊离子流实验。该功能实验测量在细胞中表达的GIRK通道（特别是GIRK1/2和GIRK1/4异源体）的活性。该实验通过量化铊离子通过被激活的钾通道的内流作为钾离子流的替代指标，从而提供通道活性（激活或抑制）的读数。每种化合物的效价（EC₅₀或IC₅₀）和效力（相对于参考化合物的激活百分比或相对于标准抑制剂的抑制百分比）均通过此实验的三次重复测量确定。 [1]
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| 动物实验 |
Animal/Disease Models: 8-10 month old C57/BL6 male mice (approximately 30 grams) [2]
Doses: 60 mg/kg Route of Administration: intraperitoneal (ip) injection Experimental Results: Most animals neither convulsed nor died. Pharmacokinetic Study: ML297 was formulated at 3.33 mg/mL in 10% Tween80 in sterile water. Male C57BL/6 mice (20-25 g) received a single intraperitoneal (i.p.) injection at a dose of 60 mg/kg. Blood (via cardiac puncture) and brain tissues were collected 30 minutes after dosing for analysis of plasma and brain concentrations. [2] Behavioral and Efficacy Studies – General: For locomotor activity (SmartCage) and rotarod tests, male C57BL/6 mice were administered ML297 (60 mg/kg, i.p.) or vehicle, and testing commenced shortly after injection. [2] Maximal Electroshock (MES) Seizure Model: Male C57BL/6 mice (8-10 months old, ~30 g) were injected intraperitoneally with ML297 (60 mg/kg), sodium valproate (150 mg/kg), or vehicle (2% DMSO in 0.5% aqueous hydroxypropyl cellulose). Thirty minutes after injection, a maximal electrical stimulus (100 mA fixed current, 50-60 Hz, 0.6 ms pulse width, 0.3 s duration) was delivered via transauricular electrodes. The time to onset of seizures was recorded. [2] Pentylenetetrazol (PTZ)-Induced Seizure Model: Male C57BL/6 mice (8-10 months old, ~30 g) were injected intraperitoneally with ML297 (60 mg/kg), sodium valproate (150 mg/kg), or the same vehicle as above. Thirty minutes later, PTZ (40 mg/kg, i.p.) was administered. The time to onset of convulsions and survival/death within a 20-minute observation period were recorded. [2] |
| 药代性质 (ADME/PK) |
In vitro experiments: ML297 showed moderate plasma protein binding in mouse plasma with a free fraction (fu) of 0.026 (2.6% free). It showed high intrinsic clearance in mouse liver microsomes with a predicted liver clearance (CLhep) of 88 mL/min/kg. Its metabolic stability was considered poor. [2] In vivo experiments (mice, single intraperitoneal injection of 60 mg/kg): The maximum free concentration (Cmax, free) in plasma was 640 nM. The maximum free concentration (Cmax, free) in brain tissue was 130 nM, with a brain tissue to plasma free concentration ratio of 0.2. The major metabolite ML297-M1 was identified as a primary alcohol generated by oxidation of the 3-methyl group on the pyrazole ring; this metabolite was inactive against GIRK1/2 and GIRK1/4. [2]
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| 毒性/毒理 (Toxicokinetics/TK) |
In escalating dose studies in mice (10, 30, 60 mg/kg, intraperitoneal injection), animals in all dose groups showed normal behavior and no obvious signs of distress. At a dose of 60 mg/kg intraperitoneal injection, ML297 resulted in a decrease in overall motor activity in mice, but had only a slight and insignificant effect on motor coordination in the rotarod test. [2]
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| 参考文献 |
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| 其他信息 |
ML297 (VU0456810) was optimized from an initial high-throughput screening compound (VU0032230) using a parallel synthesis method that focused on modifying the urea group and its linkage. The study found that the urea group linkage was crucial to the compound's activity. [1] ML297 was the starting point for the multidimensional structure-activity relationship (SAR) study described in this paper, which ultimately discovered a "molecular switch"—a subtle structural modification that could transform the skeleton from a GIRK activator into a selective inhibitor with different selectivities for GIRK1/2 and GIRK1/4. [1] This study highlights the challenges of structure-activity relationship studies, where small changes can significantly affect the pharmacological mode of action (activator or inhibitor) and channel selectivity. [1]
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| 分子式 |
C17H14F2N4O
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|---|---|---|
| 分子量 |
328.32
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| 精确质量 |
328.113
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| CAS号 |
1443246-62-5
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| 相关CAS号 |
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| PubChem CID |
56642816
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.3±0.1 g/cm3
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| 沸点 |
377.8±42.0 °C at 760 mmHg
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| 闪点 |
182.3±27.9 °C
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| 蒸汽压 |
0.0±0.9 mmHg at 25°C
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| 折射率 |
1.617
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| LogP |
4.73
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| tPSA |
62.44
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
4
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| 可旋转键数目(RBC) |
3
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| 重原子数目 |
24
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| 分子复杂度/Complexity |
433
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| 定义原子立体中心数目 |
0
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| InChi Key |
IEKSMUSSYJUQMY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H14F2N4O/c1-11-9-16(23(22-11)13-5-3-2-4-6-13)21-17(24)20-12-7-8-14(18)15(19)10-12/h2-10H,1H3,(H2,20,21,24)
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| 化学名 |
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
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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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (6.34 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。 配方 2 中的溶解度: ≥ 2.08 mg/mL (6.34 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。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (6.34 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。 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0458 mL | 15.2290 mL | 30.4581 mL | |
| 5 mM | 0.6092 mL | 3.0458 mL | 6.0916 mL | |
| 10 mM | 0.3046 mL | 1.5229 mL | 3.0458 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
ML297 selectively activates GIRK1-containing GIRKs in the absence of active GiG-proteins.ACS Chem Neurosci. 2013 Sep 18; 4(9): 1278–1286. |
Electrophysiological Characterization of ML297.ACS Chem Neurosci. 2013 Sep 18; 4(9): 1278–1286. |
ML297 is active in two models of epilepsy.ACS Chem Neurosci. 2013 Sep 18; 4(9): 1278–1286. |
IDOR-1104-0086
Maxi-K modulator 1
VU6032735
VU6080824
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