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]。