Repinotan hydrochloride
(Synonyms: BAY x 3702) 目录号 : GC64423
Repinotan hydrochloride (BAY x 3702) 是一种有效的、选择性的、可透过血脑屏障，并具有口服活性的 5-HT1A 受体激动剂，Ki 值为 0.19 nM (小牛海马)， 0.25 nM (大鼠和人类皮层) 和 0.59 nM (大鼠海马)。Repinotan hydrochloride 对其他相关受体的亲和力较弱。Repinotan hydrochloride 具有强效的神经保护作用。
Cas No.:144980-77-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >96.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Repinotan hydrochloride (BAY x 3702) is a potent, selective, brain-penetrant and orally active 5-HT1A receptor agonist, with Ki values of 0.19 nM (calf hippocampus), 0.25 nM (rat and human cortex), and 0.59 nM (rat hippocampus Repinotan hydrochloride has a weak affinity for other related receptors. Repinotan hydrochloride has pronounced neuroprotective effects[1].
[1]. A C Berends, et al. A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke. CNS Drug Rev. Winter 2005;11(4):379-402.
| Cas No. | 144980-77-8 | SDF | Download SDF |
| 别名 | BAY x 3702 | ||
| 分子式 | C21H25ClN2O4S | 分子量 | 436.95 |
| 溶解度 | 储存条件 | 4°C, away from moisture | |
| General tips | 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°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2886 mL | 11.443 mL | 22.8859 mL |
| 5 mM | 0.4577 mL | 2.2886 mL | 4.5772 mL |
| 10 mM | 0.2289 mL | 1.1443 mL | 2.2886 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats
Anesth Analg 2010 Oct;111(4):901-7.PMID:20802053DOI:10.1213/ANE.0b013e3181eac011.
Background: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. Methods: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT(1A)-R-antagonist WAY 100 135 served as controls. Results: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%-114%]) with higher doses of repinotan (2-200 μg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 μg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT(1A)-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [-100% to -44%]) was reversed by repinotan (20 μg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan. Conclusions: The 5-HT(1A)-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT(1A)-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.
Pharmacokinetics of repinotan in healthy and brain injured animals
Biopharm Drug Dispos 2005 Sep;26(6):259-68.PMID:15966026DOI:10.1002/bdd.458.
Repinotan hydrochloride (repinotan) is a highly potent and selective 5-HT(1A) full receptor agonist. The ability of repinotan to cross the blood-brain barrier (BBB) and penetrate into rat brain tissue was investigated, because rapid penetration into brain tissue is thought to be essential for neuroprotective efficacy. Intravenous (i.v.) repinotan was rapidly distributed into brain, and the distribution equilibrium between blood and brain was reached immediately after the start of infusion. Free concentrations of repinotan were identical in brain and plasma, indicating that repinotan crosses the BBB freely in both directions with diffusion as a driving force. The brain concentration of repinotan was determined by the free plasma concentration. Thus, the total plasma concentration of repinotan (sum of bound and unbound compound) is only indicative for the brain concentration as long as the unbound fraction remains constant. Metabolites of repinotan do not penetrate the BBB and are retained in the perfusing blood due to their increased polarity. The penetration of [14C] repinotan into ischemic areas of the brain was dependent on time. In studies using injured animals (pMCAO), high levels of [14C] repinotan could be detected in ischemic areas when the compound was administered up to 5 h post injury. [14C] repinotan radioactivity could no longer be detected in ischemic areas when administered 18 h after pMCA-O. After the end of infusion, repinotan was rapidly and completely eliminated from rat brains. Elimination occurred in parallel from plasma and brain with half-lives of about 1 h. In conclusion, repinotan rapidly and to a considerable extent penetrates into brain tissue of healthy and injured animals.
Effect of gender and age on the pharmacokinetics of repinotan
Clin Drug Investig 2005;25(2):125-34.PMID:17523762DOI:10.2165/00044011-200525020-00005.
Objective: Repinotan hydrochloride (repinotan) is a selective, high-affinity, full serotonin receptor agonist at the 5-HT(1A) subtype that is undergoing clinical development in acute stroke. To investigate whether gender is an important covariable for repinotan pharmacokinetics, two studies were performed in subjects of different age and gender who had been phenotyped as extensive metabolisers for cytochrome P450 (CYP)2D6 using dextromethorphan as model substrate. Subjects and methods: Both studies were placebo-controlled, double-blind, randomised, parallel-group studies. Study I was conducted in six healthy young males, five healthy elderly males, and four healthy elderly females receiving a continuous intravenous (IV) infusion of repinotan 0.45 microg/kg/h or placebo for a duration of 12 hours. Study II was performed in healthy elderly male and female volunteers aged >/=65 years with 67 subjects receiving repinotan and 34 receiving placebo. Subjects received a 12-hour infusion of repinotan at doses of 0.1, 0.3, 0.5, 1.0, 2.0 or 3.0 microg/kg/h. Results: Following IV infusion, the steady-state plasma concentration (C(ss)) for repinotan was reached after 4-6 hours consistent with its half-life of 0.8-1.8 hours. In both male and female subjects, the volume of distribution at steady-state and plasma clearance (CL) were independent of dose, indicating linear pharmacokinetics and dose-proportionality for area under the concentration-time curve (AUC) and peak plasma concentration (C(max)) over the dose range of 0.1-3.0 microg/kg/h. Compared with elderly subjects, repinotan CL was unchanged in a subgroup of young subjects. The pooled evaluation of elderly subjects (n = 67) showed that gender had no influence on the pharmacokinetics of repinotan. The ratios male : female and their 90% CIs were: 0.91 (0.789, 1.052) for dose/bodyweight-normalised C(max) (C(max,norm)), 0.95 (0.808, 1.110) for half-life, 0.97 (0.900, 1.044) for V(ss,) and 1.11 (0.923, 1.336) for CL. Conclusion: These results indicate that gender does not affect the pharmacokinetics of repinotan in healthy subjects whose age (>/=65 years) was representative of the target patient population for repinotan in acute stroke.
Oral post-lesion administration of 5-HT(1A) receptor agonist Repinotan hydrochloride (BAY x 3702) attenuates NMDA-induced delayed neuronal death in rat magnocellular nucleus basalis
Neuroscience 2001;108(4):629-42.PMID:11738499DOI:10.1016/s0306-4522(01)00444-4.
Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT)
Stroke 2009 Nov;40(11):3518-25.PMID:19745176DOI:10.1161/STROKEAHA.109.551382.
Background and purpose: Repinotan hydrochloride is a serotonin (5-HT)(1A) receptor full agonist with evidence of neuroprotection in animal models of permanent and transient focal ischemia. The purpose of this Phase IIb study was to investigate the efficacy, safety, and tolerability of a targeted exposure to repinotan in patients with acute ischemic stroke.
Methods: This was a double-blind, placebo-controlled, parallel-group, multicenter study of 681 patients stratified according to whether or not tissue plasminogen activator was administered and then randomly assigned to treatment with repinotan or placebo. A continuous 72-hour intravenous infusion of repinotan or placebo was to be started within 4.5 hours from the onset of ischemic symptoms. A Point-of-Care test was used to adjust the infusion rate if appropriate. The goal of Modified Randomized Exposure Controlled Trial (mRECT) was to show whether repinotan is statistically superior to placebo (alpha