|Cat. No. :||CS-7689|
|CAS No. :||1375466-18-4|
|M. Wt. :||330.36|
|Solubility:||DMSO: 100 mg/mL|
ACY-775 is a potent and selective inhibitor of the of histone deacetylase 6 (HDAC6), with IC50 of 7.5 nM. IC50 & Target: IC50: 7.5 nM (HDAC6) In Vitro: The HDAC6 inhibitors, ACY-775, hyperacetylate α-tubulin at a concentration of 1 μM. The histone acetylation is not affected. In vehicle-treated cells, α-tubulin is mainly present in the deacetylated form, while histone 3 is clearly acetylated. Upon treatment with ACY-775, a clear enhancement of the acetylation of α-tubulin is visible, while histone acetylation remained unaltered. Acetylation of α-tubulin is visualized by immunofluorescence and the intensity in the neurites of the neurons is quantified and normalized to the length of the fluorescent signal. In vehicle-treated DRG neurons, acetylated α-tubulin is already present. Upon treatment with ACY-775 the signal intensity of acetylated α-tubulin increase significantly. DRG neurons treat with vehicle ACY-775. Significant increase motility of mitochondria and also the total number of mitochondria within the neurites is observed compared with vehicle-treated DRG neurons. Interestingly, a significantly higher number of retrogradely transport mitochondria is observed in DRG neurons treated with ACY-775 compared with vehicle-treated cells. In Vivo: In vivo biodistribution profiles of ACY-738, ACY-775, and tubastatin A are examined after acute dosing at 5 or 50 mg/kg over 2 h. At t=30 min after acute 50 mg/kg injection, respective plasma levels of ACY-738 and ACY-775 are 515 ng/ml (1.9 μM) and 1359 ng/ml (4.1 μM). Elimination from plasma is rapid, with plasmatic half-life of 12 min and concentration below 10 ng/ml after 2 h. Nevertheless, areas under concentration time curves for brain and plasma(AUCBrain/AUCPlasma) calculate over 2 h for both ACY-738 and ACY-775 lead to ratios >1. Taken together, these results suggest that despite their short half-life, ACY-738 and ACY-775 rapidly distribute to the brain leading to a total drug exposure in CNS comparable to that of peripheral tissues. When ACY-738 (5 mg/kg) or ACY-775 (50 mg/kg) are administered repeatedly in wild-type mice at 24 h, 4 h, and 30 min before killing, significant increases in α-tubulin acetylation are observed in all tested brain regions: cortex, F2, 7=582.5, P<0.0001; hippocampus, F2, 7=260.4, P<0.0001; DRN, F2, 7=54.00,P<0.0001; and cerebellum, F2, 7=136.2, P<0.0001.
Protocol:Cell Assay: Undifferentiated RN46A-B14 cells, a line of immortalized rat raphe neuronal precursors, are grown as previously described. They are treated with 2.5 μM ACY-738, ACY-775, tubastatin A, or 0.6 μM TSA, or vehicle (0.1% DMSO) for 4 h. Samples are processed using histone extraction kit and quantified using protein assay. Animal Administration: Mice are tested for immobility in the TST using a rig from Med-Associates. At 30 min or 2 h after i.p. injection of ACY-738 (5, 50 mg/kg), ACY-775 (5, 50 mg/kg), and citalopram (0.5, 2, 20 mg/kg), a combination of the previous, or vehicle, mice are attached to the test rig and time immobile over 6 min is recorded. For open-field activity mice were injected with ACY-738 or ACY-775 at 5, 10, or 50 mg/kg or vehicle and allowed to explore. Activity was recorded using the Photobeam Activity System.
Jeanine Jochems et al. Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability. Neuropsychopharmacology. 2014 Jan; 39(2): 389–400. doi: 10.1038/npp.2013.207
Veronick Benoy, et al. Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot–Marie–Tooth Disease. Neurotherapeutics. 2017 Apr; 14(2): 417–428. doi: 10.1007/s13311-016-0501-z
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