| 规格 | 价格 | 库存 | 数量 |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 靶点 |
Orexin 1 receptor
GSK1059865 HCl (referred to as GSK1059865 in literature) targets orexin/hypocretin 1 receptor (OX1R) (highly selective for OX1R over OX2R, with inhibition of OX2R requiring micromolar concentrations while OX1R inhibition occurs at nanomolar concentrations) [2] |
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| 体外研究 (In Vitro) |
1. 在表达大鼠OX1R（rOX1R）的大鼠嗜碱性粒细胞白血病（RBL）细胞中，GSK1059865在纳摩尔浓度（0.3、1、3.3、10 nM）下即可抑制食欲素A诱导的[³H]肌醇磷酸盐（IPs）积累，展现出对OX1R的强效拮抗作用；在表达大鼠OX2R（rOX2R）的RBL细胞中，GSK1059865需在微摩尔浓度（0.1、0.3、1、3.3 μM）下才能抑制食欲素A诱导的IPs积累，证实其对OX1R的高度选择性[2]
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| 体内研究 (In Vivo) |
GSK1059865 治疗以剂量依赖性方式显着减少 CIE 暴露小鼠的乙醇饮用量。相比之下，GSK1059865 仅在最高剂量时才减少暴露于空气的小鼠的饮酒量。 GSK1059865 对蔗糖摄入量没有影响[1]。 GSK1059865 (0.3 nM-10 nM) 产生不可克服的拮抗作用，OXA EC50 剂量依赖性右移，并伴随激动剂最大反应降低。 GSK1059865 的计算 pKB 值为 8.77±0.12。 GSK1059865 (0.1-3.3 μM) 产生经典的可克服曲线，OXA EC50 平行向右移动，而不会降低激动剂最大反应[2]。腹膜内给予 GSK1059865 对育亨宾诱导的相对脑血容量反应产生区域依赖性抑制。 GSK1059865 的施用本身会在几个大脑区域产生微弱的相对脑血容量增加。 GSK1059865 预处理的动物表现出比对照组稍高的基线平均动脉血压值[3]。
1. 在经慢性间歇性乙醇（CIE）暴露的乙醇依赖小鼠中，给予GSK1059865可剂量依赖性地显著减少小鼠的自主乙醇摄入量；在空气暴露的非依赖对照小鼠中，仅最高剂量的GSK1059865能减少乙醇摄入，且该药物对两组小鼠的蔗糖摄入量均无影响[1] 2. 在雌性大鼠暴食模型中，GSK1059865以10、30 mg/kg的剂量灌胃给药，可选择性减少大鼠对高适口性食物（HPF）的强迫性摄入，不影响标准饲料的摄取，且在平行多导睡眠图实验中，该剂量未诱导大鼠出现睡眠行为[2] 3. 对给予药理应激源育亨宾（0.75 mg/kg静脉注射）的大鼠，预处理GSK1059865能显著抑制育亨宾诱导的前额-海马区及扩展杏仁核关键部位的相对脑血容量（rCBV）反应；GSK1059865不影响育亨宾诱导的血浆皮质酮释放，证实其作用机制源于中枢神经系统[3] |
| 酶活实验 |
1. OX1R/OX2R受体活性拮抗实验：培养稳定表达大鼠OX1R（rOX1R）或OX2R（rOX2R）的大鼠嗜碱性粒细胞白血病（RBL）细胞，先加入不同浓度的GSK1059865（针对rOX1R为0.3、1、3.3、10 nM，针对rOX2R为0.1、0.3、1、3.3 μM），再用食欲素A刺激细胞；通过检测[³H]肌醇磷酸盐（IPs）的放射性强度，量化食欲素受体激活后的下游信号通路水平，以此评估GSK1059865的拮抗活性；同时对rOX2R的实验数据进行Schild线性回归分析，明确GSK1059865的拮抗作用特征[2]
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| 动物实验 |
1. Ethanol dependence and intake assay in mice: Mice were first evaluated for baseline ethanol intake, then exposed to cycles of chronic intermittent ethanol (CIE) or air in inhalation chambers, with ethanol intake tested after each cycle; once CIE-exposed mice showed increased voluntary ethanol intake, GSK1059865 was administered (route not specified) at different doses, and ethanol intake (g/kg) and sucrose intake (ml) were measured; control groups included air-exposed mice treated with GSK1059865 or vehicle [1]
2. Binge eating assay in female rats: A binge eating model was established by subjecting female rats to three cycles of food restriction followed by stress (15 min of HPF exposure without access); GSK1059865 was administered by gavage at 10 and 30 mg/kg, while JNJ-10397049 (OX2R antagonist) was given intraperitoneally and SB-649868 (dual OX1/OX2R antagonist) by gavage; topiramate was used as a reference compound; polysomnography was conducted in parallel to measure sleep-inducing dose thresholds of OXR antagonists; HPF and standard food pellet intake were recorded [2] 3. fMRI stress circuit assay in rats: Functional magnetic resonance imaging (fMRI) was used to assess brain activation in rats pretreated with GSK1059865 (administration route not specified) followed by intravenous injection of yohimbine (0.75 mg/kg) as a pharmacological stressor; relative cerebral blood volume (rCBV) was measured to map brain region activation; plasma corticosterone levels were quantified at the end of the fMRI session (30 min post-yohimbine challenge) to evaluate peripheral stress responses [3] |
| 参考文献 |
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| 其他信息 |
1. The orexin/hypothalamic secretin system regulates alcohol craving and intake via OX1R; GSK1059865 is a highly selective OX1R antagonist that effectively reduces high ethanol intake in a dependence model, but has limited effect on moderate ethanol or sucrose intake, suggesting that OX1R may be a potential target for treating compulsive reward-seeking disorders such as alcoholism [1] 2. The OX1R mechanism plays an important role in binge eating behavior; selective OX1R antagonism using GSK1059865 is a novel pharmacological strategy for treating binge eating disorder and other eating disorders with compulsive components, unlike OX2R antagonists, which are ineffective for binge eating disorder [2] 3. Corticotropin-releasing factor type 1 receptor (CRF1R) and OX1R antagonists regulate stress response through different central nervous system pathways; GSK1059865 primarily inhibits stress-induced activation in the frontal-hippocampal and extended amygdala regions, while CRF1R antagonists act on the amygdala, striatum, and cingulate gyrus [3].
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| 分子式 |
C20H23BRFN3O2
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|---|---|---|
| 分子量 |
436.317927598953
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| 精确质量 |
435.095
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| CAS号 |
1191044-58-2
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| 相关CAS号 |
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| PubChem CID |
44463491
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 沸点 |
575.8±50.0 °C at 760 mmHg
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| 闪点 |
302.1±30.1 °C
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| 蒸汽压 |
0.0±1.6 mmHg at 25°C
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| 折射率 |
1.592
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| LogP |
4.41
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
5
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| 可旋转键数目(RBC) |
5
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| 重原子数目 |
27
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| 分子复杂度/Complexity |
498
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| 定义原子立体中心数目 |
2
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| SMILES |
C[C@H]1CC[C@H](N(C1)C(=O)C2=C(C(=CC=C2)F)OC)CNC3=NC=C(C=C3)Br
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| InChi Key |
TWCRHJLMMAYSTE-ZFWWWQNUSA-N
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| InChi Code |
InChI=1S/C20H23BrFN3O2/c1-13-6-8-15(11-24-18-9-7-14(21)10-23-18)25(12-13)20(26)16-4-3-5-17(22)19(16)27-2/h3-5,7,9-10,13,15H,6,8,11-12H2,1-2H3,(H,23,24)/t13-,15-/m0/s1
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| 化学名 |
[(2S,5S)-2-[[(5-bromopyridin-2-yl)amino]methyl]-5-methylpiperidin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone
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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: 3.33 mg/mL (7.63 mM) in 30 % SBE-β-CD (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
配方 2 中的溶解度: 5 mg/mL (11.46 mM) in 30% PEG300 70% (10% HP-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。 *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。 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2919 mL | 11.4595 mL | 22.9190 mL | |
| 5 mM | 0.4584 mL | 2.2919 mL | 4.5838 mL | |
| 10 mM | 0.2292 mL | 1.1459 mL | 2.2919 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) 。
 Voluntary sucrose intake (ml) for EtOH and CTL mice that received GSK1059865 treatment before drinking sucrose.Brain Res.2016 Apr 1;1636:74-80. |
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 Voluntary ethanol intake (g/kg) for EtOH and CTL mice that received GSK1059865 treatment before drinking ethanol.Brain Res.2016 Apr 1;1636:74-80. |
Orexin A-13C18,15N3 (human, rat, mouse) TFA
OX2-2303
Orexin receptor antagonist 7
Alixorexton enantiomer
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