Cort108297
目录号 : GC31392
Cort108297是一种高亲和性的特异性糖皮质激素受体(GR)拮抗剂，Ki值为0.45nM。
Cas No.:1018679-79-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Steroid receptor competition binding assays are run in a buffer containing 20 mM HEPES buffer (pH=7.6), 0.2 mM EDTA, 75 mM NaCl, 1.5 mM MgCl2, 20% glycerol, 20 mM sodium molybdate, 0.2 mM DTT, 20 μg/mL Aprotinin, and 20 μg/mL Leupeptin (assay buffer). Radiolabeled ligands are used to detect binding to cells expressing receptors including 0.25 nM [3H]Aldosterone for mineralocorticoid receptor (MR) binding, 0.3 nM [3H]Dexamethasone for GR binding, 0.36 nM [3H]Methyltrienolone for aldosterone receptor (AR) binding, and 0.29 nM [3H]methyltrienolone for PR binding. Receptors are recombinantly expressed in human embryonic kidney 293 (HEK-293) cells, and 20 μg of 293-MR lysate, 20 μg of 293-GR lysate, 22 μg of 293-AR lysate, or 40 μg of 293-PR lysate are added per well. Competing test compounds (e.g., Cort108297) are added at various concentrations from 0.01 nM to 10 μM. Nonspecific binding is determined in the presence of 500 nM Aldosterone for MR binding, 500 nM Dexamethasone for GR binding, or 500 nM methyltrienolone for AR and PR binding. The binding reactions (140 µL) are incubated overnight at 4°C, then 70 µl of cold charcoal-dextran buffer (containing per 50 mL of assay buffer, 0.75 g of Charcoal, and 0.25 g of Dextran) is added to each reaction. Plates are mixed for 8 minutes on an orbital shaker at 4°C. The plates are then centrifuged at 3000 rpm at 4°C for 10 minutes. A 120 µL aliquot of the binding reaction mixture is then transferred to another 96-well plate, and 175 µL of Wallac Optiphase Hisafe 3 scintillation fluid is added to each well. The plates are sealed and shaken vigorously using an orbital shaker. After 2 hour incubation, the plates are counted using a Wallac MicroBeta counter[1]. |
Cell experiment: | LAPC4 and CWR-22Rv1 cells are plated in standard media and incubated overnight. Cells are washed with PBS and placed into media containing charcoal stripped FBS, 10% for LAPC4 or 1%/10% for CWR-22Rv1. Cells are treated for indicated times with media changes every other day with either vehicle control or specified treatment: 1 nM R1881, 100 nM Dexamethasone, 10 µM Enzalutamide, 100 nM Mifepristone, 1 µM CORT118335, 1 µM Cort108297. For all experiments, equimolar vehicle (ethanol±DMSO) is added to every sample for equal treatment periods. Cells are plated and treated. At indicated days cells are washed, trypsinized, pelleted, and resuspended in media. Cells are then mixed 1:1 with trypan blue and viable cells are counted in a blinded fashion. Three biological replicates are assayed per condition per time point and the mean of the biological replicates is reported[2]. |
Animal experiment: | Mice[3]Forty ten-week-old, male, C57BL/6J mice are fed ad libitum a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. In addition, they receive one of the following five treatments: Cort108297 (80 mg/kg QD), Cort108297 (40 mg/kg BID), Mifepristone (30 mg/kg BID), Rosiglitazone, an oral glycemic medication (10 mg/kg QD), or vehicle (10% DMSO in 0.5% CMC). An additional control group (n=8) is fed a standard chow diet and tap water and does not receive any treatment.Rats[4]Male Sprague Dawley rats (250-275 g) are used. Forty-eight rats are matched by body weight and are administered, Cort108297 dissolved in DMSO (30mg/kg s.c.(n=10) or 60 mg/kg s.c. (n=10), Mifepristone dissolved in DMSO 10mg/kg s.c. (n=10), Imipramine dissolved in saline 10mg/kg i.p. (n=10) or vehicle DMSO s.c. (n=4) or saline i.p. (n=4). Control groups consist of both subcutaneous (s.c.) and intraperitoneal (i.p.) groups to control for the route of administration and both DMSO and saline to control for any potential differences between the compounds on neuroendocrine and behavioral stress responsiveness. |
References: [1]. Sindelar DK, et al. LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats. J Pharmacol Exp Ther. 2014 Jan;348(1):192-201. | |
Cort108297 is a specific glucocorticoid receptor (GR) antagonist. Cort108297 has a high affinity for GRs with a Ki of 0.45 nM.
In LAPC4 cells, co-treatment with Dexamethasone induces steady-state SGK1 expression 1.7-fold compared to R1881/Enzalutamide (RE) treatment alone. Addition of CORT118335 (1µM) inhibits Dexamethasone-induced SGK1 expression 50% while Cort108297 completely blocks the Dexamethasone-mediated SGK1 increase (pKLK3 expression is increased 2.5-fold by Dexamethasone compared to treatment with RE. Both Cort108297 and CORT118335 antagonize Dexamethasone-induced KLK3 expression (by 48% and 60%, respectively, pSGK1 gene expression is dramatically induced by ~100-fold compared to RE-treated cells and this induction is completely abrogated by both Cort108297 and CORT118335 (pKLK3 is also induced (7.5-fold) by Dexamethasone compared to RE in CWR-22Rv1 cells; Cort108297 and CORT118335 inhibits this induction by 70% and 75%, respectively (p<0.01)[2].
Ten-week-old, male, C57BL/6J mice are fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n=8) receive one of the following: Cort108297 (80 mg/kg QD), Cort108297 (40 mg/kg BID), Mifepristone (30 mg/kg BID), Rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either Mifepristone or Cort108297 gain significantly less weight. At the end of the four week treatment period, mice receiving Cort108297 40 mg/kg BID or Cort108297 80 mg/kg QD also have significantly lower steady plasma glucose than mice receiving vehicle[3]. Male rats are treated for five days with Mifepristone (10 mg/kg), Cort108297 (30 mg/kg and 60 mg/kg), Imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Both doses of Cort108297 potently suppress peak corticosterone responses to FST and restraint stress. However, only the higher dose of Cort108297 (60mg/kg) significantly decreases immobility in the forced swim test (FST) [4].
[1]. Sindelar DK, et al. LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats. J Pharmacol Exp Ther. 2014 Jan;348(1):192-201. [2]. Kach J, et al. Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth. Mol Cancer Ther. 2017 Aug;16(8):1680-1692. [3]. Asagami T, et al. Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice. J Nutr Metab. 2011;2011:235389. [4]. Solomon MB, et al. The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test. Horm Behav. 2014 Apr;65(4):363-71.
| Cas No. | 1018679-79-2 | SDF | |
| Canonical SMILES | O=S(N1C[C@@]2(COCC)CC3=C(N(C4=CC=C(F)C=C4)N=C3)C=C2CC1)(C5=CC=C(C(F)(F)F)C=C5)=O | ||
| 分子式 | C26H25F4N3O3S | 分子量 | 535.55 |
| 溶解度 | DMSO : 100 mg/mL (186.72 mM; Need ultrasonic) | 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。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8672 mL | 9.3362 mL | 18.6724 mL |
| 5 mM | 0.3734 mL | 1.8672 mL | 3.7345 mL |
| 10 mM | 0.1867 mL | 0.9336 mL | 1.8672 mL |
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Glucocorticoid receptor modulators
The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role.
The glucocorticoid receptor specific modulator CORT108297 reduces brain pathology following status epilepticus
Objective: Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297.
Methods: Mice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress.
Results: Treatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression.
Interpretation: Results demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus.
The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice
Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.
Glucocorticoid receptor modulators decrease alcohol self-administration in male rats
Alcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT122928, CORT108297, and CORT125134 on alcohol self-administration in nondependent (air-exposed) and alcohol-dependent (alcohol vapor-exposed) adult male rats. Different GR modulators recruit different GR-associated transcriptional cofactors. Thus, we hypothesized that these GR modulators would vary in their effects on alcohol drinking. CORT118335, CORT122928, and CORT125134 significantly reduced alcohol self-administration in both alcohol-dependent and nondependent rats. CORT108297 had no effect on alcohol self-administration in either group. The present results support the potential of GR modulators for the development of treatments for AUD. Future studies that characterize genomic and nongenomic effects of these GR modulators will elucidate potential molecular mechanisms that underlie alcohol drinking in alcohol-dependent and nondependent states.
New selective glucocorticoid receptor modulators reverse amyloid-β peptide-induced hippocampus toxicity
In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-β peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.