An FKBP51 inhibitor
SAfit2 is a potent inhibitor of FK506-binding protein 51 (FKBP51; Ki = 6 nM).1 It is highly selective for FKBP51 over FKBP52 (Ki = >50,000 nM) and has increased brain permeability in comparison to SAfit1. SAfit2 (20 mg/kg) enhances HPA axis suppression in mice by decreasing plasma corticosterone levels to a greater extent than in control mice following dexamethasone administration. It also does not increase plasma corticosterone levels as high as in control mice following subsequent administration of corticotropin-releasing factor (CRF). It decreases the time spent immobile in the forced swim test and increases the time spent in the open arms of the elevated plus maze, indicating antidepressant-like and anxiolytic-like activity, respectfully.2
1.Gaali, S., Kirschner, A., Cuboni, S., et al.Selective inhibitors of the FK506-binding protein 51 by induced fitNat. Chem. Biol.11(1)33-37(2015) 2.Hartmann, J., Wagner, K.V., Gaali, S., et al.Pharmacological inhibition of the psychiatric risk factor FKBP51 has anxiolytic propertiesJ. Neurosci.35(24)9007-9016(2015)
Cell experiment: | Primary EDL myotubes are exposed to 0.6?μM SAFit2 or DMSO (vehicle) overnight. The following day, cells are serum-starved in low glucose (1000?mg/L) DMEM for 4?h with SAFit2 or DMSO, and are subsequently collected for the rapid preparation of the plasma membrane fraction. The membrane fraction is used in subsequent Western blot assays for the detection of GLUT4[2]. |
Animal experiment: | Male C57BL/6N mice at the age of 12 to 15 weeks are used. The mice are held under standard conditions (12 h light/dark cycle, lights on at 08:00 A.M.; temperature 23±2°C), are single housed and acclimatized to the room for 2 weeks before the commencing experiments. Food and tap water are available ad libitum. Animals receive a bilateral microinjection into the basolateral amygdala (BLA) (0.5 μL per side) of vehicle or SAFit2 (20 mg/kg BW) 16 h before the start of the test. The effects on anxiety-related behavior is analyzed (n=14 per group) 16 h after the application[3]. |
参考文献: [1]. Gaali S, et al. Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51. J Med Chem. 2016 Mar 24;59(6):2410-22. | |
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