XE 991 dihydrochloride
目录号 : GC11919
XE 991 dihydrochloride是一种状态依赖性、选择性的KCNQ通道抑制剂，可抑制M电流、KCNQ2+KCNQ3、KCNQ2及KCNQ1（KvLQT1）， IC50分别为0.98±0.15μM、0.6±0.01μM、0.71±0.07μM和0.75±0.05μM。
Cas No.:122955-13-9
Sample solution is provided at 25 µL, 10mM.
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XE 991 dihydrochloride is a state-dependently and selective inhibitor of KCNQ channels that inhibits the M-current, KCNQ2+KCNQ3, KCNQ2, and KCNQ1 (KvLQT1) with IC50 values of 0.98±0.15μM, 0.6±0.01μM, 0.71±0.07μM, and 0.75±0.05μM, respectively[1-2]. XE 991 dihydrochloride suppresses the anti-contractile effect of perivascular adipose tissue (PVAT), where voltage-gated KCNQ channels play a key role in regulating vascular tone[3].
In vitro, treatment of mouse smooth-muscle cells with increasing concentrations of XE 991 dihydrochloride (3, 10, 100μM) inhibited the outward current in a concentration-dependent manner, and the block was voltage-independent[4]. Large neurons treated with 10μM nicotine every 3.5 minutes were subjected to 10μM XE 991 dihydrochloride treatment, which significantly inhibited nicotine response induced by nicotine in a reversible manner[5]. Treatment of isolated bladder strips with 10µM XE 991 dihydrochloride simultaneously increased both contraction amplitude and mean tension, but preferentially augmented the number of stimulus-evoked twitches rather than their individual amplitude[6].
In vivo, male Swiss mice given XE 991 dihydrochloride (2.5mg/kg; i.p.) or vehicle 15min before behavioral testing displayed short-term memory after 5 or 10min of object-recognition (OR) training comparable to that of 15min controls, and the 10min group also achieved equivalent long-term memory[7]. Male C57BL/6 mice subjected to bath application of XE 991 dihydrochloride (3μM) exhibited complete reversal of the fasudil (30μM)-induced augmentation of Kv7.4 currents in dorsal raphe nucleus (DRN) serotonin (5-HT) neurons[8].
References:
[1] Wang HS, Pan Z, Shi W, et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science. 1998;282(5395):1890-1893.
[2] Greene DL, Kang S, Hoshi N. XE991 and Linopirdine Are State-Dependent Inhibitors for Kv7/KCNQ Channels that Favor Activated Single Subunits. J Pharmacol Exp Ther. 2017;362(1):177-185.
[3] Tsvetkov D, Tano JY, Kassmann M, Wang N, Schubert R, Gollasch M. The Role of DPO-1 and XE991-Sensitive Potassium Channels in Perivascular Adipose Tissue-Mediated Regulation of Vascular Tone. Front Physiol. 2016;7:335.
[4] Yeung SY, Greenwood IA. Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells. Br J Pharmacol. 2005;146(4):585-595.
[5] Sato A, Kojima F, Hayashi T, et al. The KCNQ channel inhibitor XE991 suppresses nicotinic acetylcholine receptor-mediated responses in rat intracardiac ganglion neurons. Pharmacol Rep. 2022;74(4):745-751.
[6] Rode F, Svalø J, Sheykhzade M, Rønn LC. Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder. Eur J Pharmacol. 2010;638(1-3):121-127.
[7] Fontán-Lozano A, Suárez-Pereira I, Delgado-García JM, Carrión AM. The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease. Hippocampus. 2011;21(1):22-32.
[8] Zhao C, Su M, Wang Y, et al. Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons. Front Cell Neurosci. 2017;11:405.
XE 991 dihydrochloride是一种状态依赖性、选择性的KCNQ通道抑制剂，可抑制M电流、KCNQ2+KCNQ3、KCNQ2及KCNQ1（KvLQT1）， IC50分别为0.98±0.15μM、0.6±0.01μM、0.71±0.07μM和0.75±0.05μM[1-2]。XE 991 dihydrochloride还可抑制血管周围脂肪组织（PVAT）的抗收缩效应，其中电压门控KCNQ通道在血管张力调节中发挥关键作用[3]。
体外实验表明，用递增浓度（3、10、100μM）的XE 991 dihydrochloride处理小鼠平滑肌细胞，可浓度依赖性地抑制外向电流，且该阻断作用与电压无关[4]。对每3.5min施加10μM尼古丁处理的大神经元再给予10μM XE 991 dihydrochloride，可显著且可逆地抑制尼古丁诱发的反应[5]。用10μM XE 991 dihydrochloride处理离体膀胱组织条，可同步增加收缩幅度与平均张力，但主要增强刺激诱发抽动的次数，而非单次幅度[6]。
体内实验中，雄性Swiss小鼠在行为测试前15min腹腔注射XE 991 dihydrochloride（2.5mg/kg）或对照后，接受5或10min物体识别（OR）训练的小鼠在短期记忆（STM）上与训练15min的对照组相当，且10min组还获得了等效的长期记忆（LTM）[7]。雄性C57BL/6小鼠经浴槽灌流3μM XE 991 dihydrochloride后，可完全逆转背缝核（DRN）5-羟色胺（5-HT）神经元中由fasudil（30μM）引起的Kv7.4电流增强[8]。
| Cell experiment [1]: | |
Cell lines | Large neurons |
Preparation Method | XE 991 dihydrochloride was first dissolved in 100% DMSO to prepare a 10mM stock solution and then diluted in extracellular solution to the required concentration. Large neurons were treated with 10µM nicotine every 3.5min, and 10µM XE 991 dihydrochloride was applied 1min before the second nicotine application. |
Reaction Conditions | 10µM; 14min |
Applications | XE 991 dihydrochloride, applied 1min before the second nicotine pulse, markedly suppressed the nicotinic response. With XE 991 dihydrochloride still present, the current evoked by the third agonist application was virtually identical to that of the second. After washout of XE 991 dihydrochloride, nicotine-induced responses fully recovered. |
| Animal experiment [2]: | |
Animal models | male Swiss mice |
Preparation Method | Fifteen minutes before behavioral or electrophysiological testing, XE 991 dihydrochloride (2.5mg/kg; i.p.) or saline alone was administered to the mice. Three groups of mice were then submitted to a 5, 10, or 15min training session for object recognition (OR) memory, and short- or long-term memory (STM and LTM, respectively) was then tested 1 or 24 hours after the training session. |
Dosage form | 2.5mg/kg; i.p. |
Applications | When administrated XE 991 dihydrochloride 15min before the 5 or 10min OR training session, STM was similar to that observed in saline-injected mice trained for 15min. By contrast, only the XE 991 dihydrochloride injected mice subjected to a 10min training session for OR displayed similar LTM. |
References: | |
| Cas No. | 122955-13-9 | SDF | |
| 化学名 | 10,10-bis(pyridin-4-ylmethyl)anthracen-9(10H)-one dihydrochloride | ||
| Canonical SMILES | O=C(C1=CC=CC=C12)C3=CC=CC=C3C2(CC4=CC=NC=C4)CC5=CC=NC=C5.Cl.Cl | ||
| 分子式 | C26H20N2O.2HCl | 分子量 | 449.37 |
| 溶解度 | 2mg/ml in DMSO | 储存条件 | Store at -20°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2253 mL | 11.1267 mL | 22.2534 mL |
| 5 mM | 0.4451 mL | 2.2253 mL | 4.4507 mL |
| 10 mM | 0.2225 mL | 1.1127 mL | 2.2253 mL |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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- Purity: >98.00%
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