ACT-462206 是一种口服有效的双Orexin 1/Orexin 2受体拮抗剂，IC50分别为 60 nM (Orexin 1) 和 11 nM (Orexin 2)。ACT-462206 能穿过血脑屏障，可用于失眠、压力/焦虑相关障碍和成瘾研究。
| 生物活性 | ACT-462206 is an orally active and potent dualOrexin 1/Orexin 2receptor antagonist withIC50s of 60 nM (Orexin 1) and 11 nM (Orexin 2), respectively. ACT-462206 exhibits brain penetration properties, and can be used for insomnia, stress/anxiety-related disorders and addiction research[1]. |
| IC50& Target | |
体外研究
(In Vitro) | Orexins are released in a Ca2+-sensitive manner at axonal terminals and can then bind to two closely related G-protein-coupled receptors (GPCRs): orexin receptor type 1 (OX1) and orexin receptor type 2 (OX2)[1].
ACT-462206 shows binding affinity with Kbs of 17 nM (hOX1), 2.4 nM (hOX2), 28 nM (rOX1), 9.9 nM (rOX2), 27 nM (dOX1), 4.2 nM (dOX2), respectively[1].
ACT-462206 inhibits Orexin activity with IC50s of 60 nM (hOX1), 11 nM (hOX2), 48 nM (rOX1), 9.6 nM (rOX2), 68 nM (dOX1), 26 nM (dOX2), respectively[1].
ACT-462206 inhibits CYP450 3A4T and 3A4M with IC50s of 15 μM and 29 μM, respectively[1].
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体内研究
(In Vivo) | ACT-462206 (compound 24) (100 mg/kg; p.o.; sampling at 3 h) can go cross blood brain barrier, with concentrations are 2267 ng/mL and 1219 ng/g in plasma and brain, respectively in male Wistar rats[1].
ACT-462206 (10-300 mg/kg; p.o.; single dose) shows sleep-promoting effects in male Wistar rats and in male Beagle dogs, with decreasing wakefulness and increasing non-rapid eye movement (non-REM) and REM sleep[1].
ACT-462206 (100, 300 mg/kg; p.o.; single dose) exerts anxiolytic-like effects, decreases the fear-potentiated startle reflexes in response to a sudden loud noise in rats, reduces the socialstress-induced increases of locomotion, body temperature, and heart rate[1].
Pharmacokinetics in different species[1]
| Route | Dose (mg/kg) | AUC (ngoh/mL) | CL (mL/min/kg) | Vss(L/kg) | t1/2(h) | cmax(ng/mL) | tmax(h) | F1/2(%) | | rat | i.v. | 1 | 586 | 29 | 1.8 | 1.9 | / | / | / | | p.o. | 10 | 2310 | / | / | / | 1600 | 0.5 | 39 | | dog | i.v. | 1 | 1490 | 11 | 1.4 | 1.7 | / | / | / | | p.o. | 3 | 2750 | / | / | / | 426 | 0.5 | 52 |
| Animal Model: | Male Wistar rats[1] | | Dosage: | 0, 10, 30, 100, 300 mg/kg | | Administration: | Oral gavage; single dose | | Result: | Decreased the latency to the first persistent episode of non-REM sleep (60 s) and the first persistent episode of REM sleep (30 s).
Dose-dependently decreased total wake time and behavioral home cage activity (one-way ANOVA; p<0.001), while increasing REM and non-REM sleep times. |
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| Clinical Trial | |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, protect from light *In solvent : -80°C, 6 months; -20°C, 1 month (protect from light) |
| 溶解性数据 | In Vitro: DMSO : ≥ 100 mg/mL(257.41 mM) *"≥" means soluble, but saturation unknown. 配制储备液 | 1 mM | 2.5741 mL | 12.8707 mL | 25.7414 mL | | 5 mM | 0.5148 mL | 2.5741 mL | 5.1483 mL | | 10 mM | 0.2574 mL | 1.2871 mL | 2.5741 mL |
*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℃, 6 months; -20℃, 1 month (protect from light)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.5 mg/mL (6.44 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (6.44 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.5 mg/mL (6.44 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (6.44 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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