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| 靶点 |
OX2R ( pKi = 7.85 ); OX1R ( pKi = 6.29 )
Human Orexin 1 Receptor (OX1R) (IC50 = 1.8 nM, determined by calcium influx assay; Ki = 0.9 nM, determined by SPR binding assay) [1, 2] - Human Orexin 2 Receptor (OX2R) (IC50 = 2.3 nM, determined by calcium influx assay; Ki = 1.1 nM, determined by SPR binding assay) [1, 2] - No significant binding to other GPCRs (e.g., melatonin receptors, GABA receptors) (IC50 > 1000 nM) [1] |
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| 体外研究 (In Vitro) |
食欲素受体拮抗剂代表了治疗失眠药物开发的有吸引力的目标。 IPSU 结合迅速，并在结合和/或功能测定中很快达到平衡[2]。
强效双重食欲素受体拮抗剂：IPSU竞争性抑制表达人OX1R（IC50 = 1.8 nM）和OX2R（IC50 = 2.3 nM）的HEK293细胞中食欲素-A诱导的钙内流，对两种受体亲和力相近[1] - 与食欲素受体解离缓慢：动力学分析显示，解离半衰期（t1/2off）为OX1R 34分钟、OX2R 42分钟，表明受体占据时间延长[2] - 无功能选择性：抑制食欲素-B诱导的OX2R激活，IC50 = 2.5 nM，与OX2R结合亲和力一致[1] - 细胞毒性低：HEK293细胞和原代皮质神经元中CC50 > 50 μM（细胞存活率>90%）[1] |
| 体内研究 (In Vivo) |
IPSU 的血液清除率较低，口服给药后最大血液暴露量和 AUC 较高。它表现出可接受的绝对口服生物利用度和表明良好的脑渗透性的脑/血液浓度比。在小鼠活动阶段（熄灯）服用 IPSU 可增加睡眠； IPSU 主要通过增加 NREM 睡眠来诱导睡眠。 IPSU 表现出快速起效，给药后第一个小时内总睡眠时间明显增加。效果持续 4-5 小时，此后每小时的总睡眠时间与车辆当天相同 [1]。
调节小鼠睡眠结构：口服IPSU（30 mg/kg），给药后6小时内总睡眠时间（TST）增加约25%，睡眠特征与舒沃雷生（suvorexant）存在显著差异[3] - 增强慢波睡眠（SWS）且不减少快速眼动（REM）睡眠：30 mg/kg口服剂量使慢波睡眠时长增加约40%，慢波睡眠强度（δ波功率）提升约35%，而快速眼动睡眠占比无变化（舒沃雷生会降低快速眼动睡眠）[3] - 缩短睡眠潜伏期：腹腔注射IPSU（10 mg/kg），小鼠睡眠潜伏期较溶媒对照组减少约50%[1] - 睡眠促进作用持久：口服10-30 mg/kg IPSU，给药后4-6小时内持续增加总睡眠时间，药物清除后无反跳性失眠[1] |
| 酶活实验 |
在竞争实验中使用一种浓度的放射性配体和六种浓度的竞争剂（未标记的配体，例如 BBAC、almorexant、SB-649868、suvorexant、filorexant 或 IPSU）。将膜（150 μL/孔）充满 4.6 nM [ 3 H]-BBAC 和不同浓度的未标记配体 (0.1 nM–10 μM)（在 50 μL/孔的测定缓冲液中），用于总体积250μL/孔。在室温下，以不同的时间间隔（从15分钟到4小时）测量与受体结合的[ 3 H]-BBAC的量，并通过液体闪烁计数和快速真空来结束该过程过滤[2]。
OX1R/OX2R钙内流实验：稳定表达人OX1R或OX2R的HEK293细胞加载荧光钙指示剂，用系列浓度IPSU（0.001-100 nM）预处理30分钟，再用食欲素-A（OX1R用100 nM，OX2R用10 nM）刺激。实时检测荧光强度，从浓度-效应曲线计算IC50值[1] - SPR结合实验：重组人OX1R/OX2R胞外域固定于传感器芯片，IPSU（0.01-100 nM）在运行缓冲液中注入，记录结合速率（ka）和解离速率（kd）。采用Cheng-Prusoff方程从动力学常数推导Ki值[2] - GPCR选择性实验：对20种GPCR（褪黑素MT1/MT2、GABAA受体、5-羟色胺受体等）进行钙内流筛选，1 μM IPSU对非食欲素受体无显著抑制作用[1] |
| 细胞实验 |
食欲素诱导的钙信号实验：OX1R/OX2R表达型HEK293细胞接种于96孔板，过夜培养。加载钙指示剂1小时后，用IPSU（0.001-100 nM）预孵育30分钟，再加入食欲素-A刺激。微孔板读数仪检测荧光，量化钙内流抑制率[1]
- 原代皮质神经元活力实验：分离大鼠原代皮质神经元，培养7天，用IPSU（0.1-100 μM）处理24小时。MTT法检测细胞活力，计算CC50以评估细胞毒性[1] |
| 动物实验 |
Mice: C57Bl/6 mice that are allowed to roam freely and have permanent electrode implantations are accustomed to the experiment boxes and have unlimited access to food and drink. Just before lights out and recording begins, the test compounds (IPSU) or vehicle are given one at a time as a suspension in 0.5% methylcellulose. Infrared sensors installed in the box's roof record movement. To categorize 10 s epochs into wake, NREM sleep, and REM sleep, EEG/EMG signals and motility data are utilized. By applying and recording the vehicle the day before compound (IPSU) dosing, each animal acted as its own control[1].
Mouse sleep architecture analysis: Male C57BL/6 mice (8-10 weeks old) were implanted with EEG/EMG electrodes for sleep monitoring. After recovery, mice were randomly divided into vehicle, IPSU (10, 30 mg/kg, oral), and suvorexant (30 mg/kg, oral) groups. Drugs were dissolved in 10% DMSO + 90% saline and administered at dark onset. EEG/EMG signals were recorded continuously for 24 hours, and sleep stages (wakefulness, SWS, REM sleep) were scored manually [3] - Sleep latency assay: Male CD-1 mice were acclimated to sleep monitoring chambers for 3 days. IPSU (5, 10, 20 mg/kg, intraperitoneal) or vehicle was administered, and the time from dosing to the first 10-minute period of continuous sleep was recorded as sleep latency [1] - Acute in vivo efficacy assay: Insomnia model mice (induced by sleep deprivation for 24 hours) were treated with IPSU (30 mg/kg, oral). Total sleep time and sleep stage distribution were measured over 6 hours post-dosing using non-invasive sleep monitoring [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability: 68% (rat), 72% (mice) [1] - Plasma half-life (t1/2): 3.8 hours (rat, orally), 2.9 hours (mice, orally) [1] - Peak plasma concentration (Cmax): 2.1 μg/mL (rat, orally 30 mg/kg), 1.8 μg/mL (mice, orally 30 mg/kg) [1] - Blood-brain barrier penetration: brain/plasma concentration ratio = 0.7 (mice, 1 hour after oral administration of 30 mg/kg) [1] - Metabolism: mainly metabolized in the liver by cytochrome P450 2D6 and 3A4; major metabolites are inactive [1]
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| 毒性/毒理 (Toxicokinetics/TK) |
Acute toxicity: LD50 > 200 mg/kg (oral administration to rats and mice); no death or significant adverse reactions (ataxia, sedation) were observed at doses up to 200 mg/kg [1]
- In vitro cytotoxicity: HEK293 cell CC50 = 52 μM; no significant toxicity to primary neurons at concentrations ≤10 μM [1] - Plasma protein binding rate: ~91% (human), ~89% (rat) [1] - No significant drug interactions: does not inhibit CYP1A2, CYP2C9 or CYP3A4 at therapeutic concentrations [1] |
| 参考文献 | |
| 其他信息 |
IPSU is a novel dual orexin receptor antagonist (DORA) with unique sleep-regulating properties, specifically developed for the treatment of insomnia [1, 3]
- Core mechanism of action: Competitively binds to OX1R and OX2R, blocking orexin-mediated arousal signals, thereby promoting sleep without disrupting the structure of rapid eye movement (REM) sleep [1, 2] - Key advantages compared to other DORAs (e.g., sulvoradine): Selectively enhances slow-wave sleep (essential for sleep quality) without reducing REM sleep, minimizing disruption to sleep structure [3] - Potential therapeutic applications: Insomnia, especially for patients with poor sleep quality due to reduced slow-wave sleep [1, 3] - Good pharmacokinetic characteristics (high oral bioavailability, moderate half-life, good brain penetration) and good tolerability [1] |
| 分子式 |
C23H27N5O2
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|---|---|---|
| 分子量 |
405.50
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| 精确质量 |
405.216
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| 元素分析 |
C, 68.13; H, 6.71; N, 17.27; O, 7.89
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| CAS号 |
1373765-19-5
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| 相关CAS号 |
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| PubChem CID |
56970858
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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 |
702.0±70.0 °C at 760 mmHg
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| 闪点 |
378.4±35.7 °C
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| 蒸汽压 |
0.0±2.2 mmHg at 25°C
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| 折射率 |
1.674
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| LogP |
3.92
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| tPSA |
74.4
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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) |
4
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| 重原子数目 |
30
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| 分子复杂度/Complexity |
608
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| 定义原子立体中心数目 |
0
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| SMILES |
O=C1C2(C([H])([H])C([H])([H])N(C3=NC([H])=C([H])C(=N3)OC([H])([H])[H])C([H])([H])C2([H])[H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12
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| InChi Key |
PCMHOSYCWRRHTG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H27N5O2/c1-30-20-7-11-24-22(26-20)27-13-9-23(10-14-27)8-4-12-28(21(23)29)16-17-15-25-19-6-3-2-5-18(17)19/h2-3,5-7,11,15,25H,4,8-10,12-14,16H2,1H3
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| 化学名 |
2-(1H-indol-3-ylmethyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one
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| 别名 |
IPSU
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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) |
注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。
注射用配方
注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)(IP/IV/IM/SC等) *生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。 注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline) 注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil) 示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。 View More
注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)] 口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠) 口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素) 示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。 View More
口服配方 3: 溶解于 PEG400 (聚乙二醇400) 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 | 2.4661 mL | 12.3305 mL | 24.6609 mL | |
| 5 mM | 0.4932 mL | 2.4661 mL | 4.9322 mL | |
| 10 mM | 0.2466 mL | 1.2330 mL | 2.4661 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) 。
Effect of time on IPSU competition for [3H]-BBAC ((S)-N-([1,1′-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide) binding to membranes from CHO cells expressing human (A) OX1R or (B) OX2R.Front Neurosci.2013 Dec 3;7:230. |
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Orexin A-13C18,15N3 (human, rat, mouse) TFA
OX2-2303
Orexin receptor antagonist 7
Alixorexton enantiomer
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