XE 991 dihydrochloride

The KCNQ potassium channels are neuronal modulators which combine with other KQT or KCNE channels to form heteromultimers. XE 991 is a blocker of KCNQ channels that potently inhibits KCNQ1 and 2 homomeric channels (IC50 = 0.75 and 0.71 μM, respectively) as well as KCNQ2+3 heteromultimers (IC50 = 0.6 μM).[1] It much less effectively blocks eag, erg, and elk channels. The effectiveness of XE 991 against KCNQ channels depends on partners or accessory proteins.[2] Through these actions, XE 991 enhances acetylcholine release from rat brain slices (EC50 = 490 nM) and shows good in vivo potency and duration of action, suggesting utility in Alzheimer’s disease therapeutics.[3] While early studies focused on actions in the central nervous system, XE 991 can be used to explore the roles of KCNQ channels in neuronal regulation throughout the body.[4]

Reference:
[1]. Wang, H.S., Pan, Z., Shi, W., et al. KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M-channel. Science 282(5395), 1890-1893 (1998).
[2]. Wang, H.S., Brown, B.S., McKinnon, D., et al. Molecular basis for differential sensitivity of KCNQ and IKs channels to the cognitive enhancer XE991. Molecular Pharmacology 57(6), 1218-1223 (2000).
[3]. Zaczek, R., Chorvat, R.J., Saye, J.A., et al. Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: Comparison to linopirdine. Journal of Pharmacology and Experimental Therapeutics 285(2), 724-730 (1998).
[4]. Hawryluk, J.M., Moreira, T.S., Takakura, A.C., et al. KCNQ channels determine serotonergic modulation of ventral surface chemoreceptors and respiratory drive. Journal of Neuroscience 32(47), 16943-16952 (2012).