Org-26576
目录号 : GC30852
Org26576是AMPA受体的正变构调节剂。
Cas No.:1026791-61-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Rats: Saline and Org-26576 (10 mg/kg) are administered, by intraperitoneal injection, 25 min before acute swim stress. Briefly, rats are subjected to a swim stress session for 5 min and sacrificed by decapitation 15 min after the end of the swim session. Brain regions are immediately dissected, frozen on dry ice and stored at -80°C[3]. Mice: Org-26576 (0.1, 1, 10 mg/kg) and Org 24448 (3, 10, 30 mg/kg) or vehicle (5% Mulgofenesaline) are administered intraperitoneally (i.p.) 10 min prior to the administration of the 14C-2-deoxyglucose. All drugs/vehicle are administered in the contralateral side of the abdomen to the 14C-2-deoxyglucose (2-DG) i.p. injection. A separate group of animals is also administered the AMPA receptor antagonist NBQX. NBQX (10 mg/kg) is injected either alone or 10 min prior to the administration of Org-26576 (10 mg/kg i.p.), Org 24448 (10 mg/kg i.p.) or vehicle (5% Mulgofenesaline i.p.). For each drug dose administered nZ5e7. The behavioural effects of all drugs administered are monitored throughout the entirety of procedure, and any alterations in behaviour noted[1]. |
References: [1]. Jordan GR, et al. Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. Neuropharmacology. 2005 Aug;49(2):254-64. | |
Org 26576 is a AMPA receptor positive allosteric modulator.
Org 26576 represents structurally a distinct chemical series derived from the first generation ampakine CX516 and displays 10-30 fold greater potency when compared to CX516 in potentiating AMPA-mediated electrophysiological responses with an EC50 of 8-16 μM in rat hippocampal primary cultured neurons. Org 26576 demonstrates selectivity for AMPA receptors when tested at 10 μM against >60 molecular targets including G-Protein Coupled Receptors, ion channels and kinases[1].
Org 26576 (1 mg/kg) produces significant increases in the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus in mice[1]. Chronic administration of Org 26576 increases progenitor cell proliferation in dentate gyrus (approximately 40%) and in prelimbic cortex (approximately 35%) at the 10-mg/kg dosage. Cells born in response to chronic Org 26576 in dentate gyrus exhibits increased rates of survival (approximately 30%) with the majority of surviving cells expressing a neuronal phenotype[2]. AMPA receptor potentiation by Org 26576 exerts a positive modulatory influence on brain derived neurotrophic factor (BDNF) expression during ongoing neuronal activity. Total BDNF mRNA levels are significantly increased in the hippocampus of animals exposed to the combination of Org 26576 and stress[3].
[1]. Jordan GR, et al. Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. Neuropharmacology. 2005 Aug;49(2):254-64. [2]. Su XW, et al. Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus. Psychopharmacology (Berl). 2009 Oct;206(2):215-22. [3]. Fumagalli F, et al. The AMPA receptor potentiator Org 26576 modulates stress-induced transcription of BDNF isoforms in rat hippocampus. Pharmacol Res. 2012 Feb;65(2):176-81.
| Cas No. | 1026791-61-6 | SDF | |
| Canonical SMILES | O=C1N2[C@](CCC2)([H])COC3=NC=CC=C13 | ||
| 分子式 | C11H12N2O2 | 分子量 | 204.23 |
| 溶解度 | DMSO : 25 mg/mL (122.41 mM) | 储存条件 | Store at -20°C |
| 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 | 4.8964 mL | 24.4822 mL | 48.9644 mL |
| 5 mM | 0.9793 mL | 4.8964 mL | 9.7929 mL |
| 10 mM | 0.4896 mL | 2.4482 mL | 4.8964 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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；
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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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Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial
Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.
The ampakine, Org 26576, bolsters early spatial reference learning and retrieval in the Morris water maze: a subchronic, dose-ranging study in rats
Ampakines have shown beneficial effects on cognition in selected animal models of learning. However, their ability to modify long-term spatial memory tasks has not been studied yet. This would lend credence to their possible value in treating disorders of cognition. We evaluated the actions of subchronic Org 26576 administration on spatial reference memory performance in the 5-day Morris water maze task in male Sprague-Dawley rats, at doses of 1, 3 and 10 mg/kg twice daily through intraperitoneal injection over 12 days. Org 26576 exerted a dose and time-dependent effect on spatial learning, with dosages of 3 and 10 mg/kg significantly enhancing acquisition on day 1. Globally, escape latency decreased significantly as the training days progressed in the saline and Org 26576-treated groups, indicating that significant and equal learning had taken place over the learning period. However, at the end of the learning period, all doses of Org 26576 significantly improved spatial memory storage/retrieval without confounding effects in the cued version of the task. Org 26576 offers early phase spatial memory benefits in rats, but particularly enhances search accuracy during reference memory retrieval. These results support its possible utility in treating disorders characterized by deficits in cognitive performance.
Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography
AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.
Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus
Rationale: Currently available antidepressants upregulate hippocampal neurogenesis and prefrontal gliogenesis after chronic administration, which could block or reverse the effects of stress. Allosteric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators (ARPs), which have novel targets compared to current antidepressants, have been shown to have antidepressant properties in neurogenic and behavioral models.
Objectives: This study analyzed the effect of the ARP Org 26576 on the proliferation, survival, and differentiation of neurons and glia in the hippocampus and prelimbic cortex of adult rats.
Materials and methods: Male Sprague-Dawley rats received acute (single day) or chronic (21 day) twice-daily intraperitoneal injections of Org 26576 (1-10 mg/kg). Bromodeoxyuridine (BrdU) immunohistochemistry was conducted 24 h or 28 days after the last drug injection for the analysis of cell proliferation or survival, respectively. Confocal immunofluorescence analysis was used to determine the phenotype of surviving cells.
Results: Acute administration of Org 26576 did not increase neuronal cell proliferation. However, chronic administration of Org 26576 increased progenitor cell proliferation in dentate gyrus (approximately 40%) and in prelimbic cortex (approximately 35%) at the 10-mg/kg dosage. Cells born in response to chronic Org 26576 in dentate gyrus exhibited increased rates of survival (approximately 30%) with the majority of surviving cells expressing a neuronal phenotype.
Conclusion: Findings suggest that Org 26576 may have antidepressant properties, which may be attributed, in part, to upregulation of hippocampal neurogenesis and prelimbic cell proliferation.
The AMPA receptor potentiator Org 26576 modulates stress-induced transcription of BDNF isoforms in rat hippocampus
Brain derived neurotrophic factor (BDNF) is a key mediator of brain plasticity. The modulation of its expression and function is important for cognition and represents a key strategy to enhance neuronal resilience. Within this context, there exists a close interaction between glutamatergic neurotransmission and BDNF activity towards regulating cellular homeostasis and plasticity. The aim of the current study was to investigate the ability of the AMPA receptor potentiator Org 26576 to modulate BDNF expression in selected brain regions under basal conditions or in response to an acute swim stress. Rats subjected to a single intraperitoneal injection with Org 26576 (10mg/kg) or saline were exposed to a swim stress session (5 min) and sacrificed 15 min after the end of stress. Real-time PCR assay was used to determine changes in BDNF transcription in different brain regions. Total BDNF mRNA levels were significantly increased in the hippocampus of animals exposed to the combination of Org 26576 and stress whereas, in prefrontal and frontal cortices, BDNF mRNA levels were modulated by the acute stress, independently from drug treatment. The analysis of BDNF transcripts in the hippocampus revealed a major contribution of exons I and IV. Our results suggest that AMPA receptor potentiation by Org 26576 exerts a positive modulatory influence on BDNF expression during ongoing neuronal activity. Given that these mechanisms are critical for neuronal plasticity, we hypothesized that such changes may facilitate learning/coping mechanisms associated with a mild stressful experience.