XE 991 dihydrochloride

KCNQ/M currents in sensory neurons: significance for pain therapy.[Pubmed:12904483]

J Neurosci. 2003 Aug 6;23(18):7227-36.

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.

Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991.[Pubmed:10825393]

Mol Pharmacol. 2000 Jun;57(6):1218-23.

Channels formed by coassembly of the KCNQ1 (KvLQT1) subunit and the minK subunit underlie slowly activating cardiac delayed rectifier (I(Ks)) in the heart, whereas two other members of the KCNQ channel family, KCNQ2 and KCNQ3, coassemble to underlie the M current in the nervous system. Because of their important physiological function, KCNQ channels have potential as drug targets, and an understanding of possible mechanisms that would enable tissue-specific targeting of these channels will be of significant value to drug development. In this study, we examined the role of the minK subunit in determining the response of KCNQ1 channels to blockade by the cognitive enhancer XE991. Coexpression with minK markedly decreased the sensitivity of KCNQ1 to blockade by XE991. When measured at the end of a 500-ms step, XE991 blockade of the KCNQ1+minK current had a K(D) value of 11.1 +/- 1.8 microM, approximately 14-fold less sensitive than the block of the KCNQ1 current (K(D) = 0.78 +/- 0.05 microM). In addition, XE991 reduced activation and deactivation time constants and caused a rightward shift in the activation curve of KCNQ1+minK, but affected none of these parameters for KCNQ1 alone. Also, XE991 block of KCNQ1+minK, but not of KCNQ1, was time- and voltage-dependent. We conclude that the presence of minK in the I(Ks) channel complex gives rise to differential sensitivity of KCNQ and I(Ks) channels to blockade by XE991. Our results have implications for drug development by demonstrating the important potential role of accessory subunits in determining the pharmacological properties of KCNQ channels.

KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel.[Pubmed:9836639]

Science. 1998 Dec 4;282(5395):1890-3.

The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.

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.[Pubmed:9580619]

J Pharmacol Exp Ther. 1998 May;285(2):724-30.

Linopirdine (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, DUP996) is an extensively studied representative of a class of cognition enhancing compounds that increase the evoked release of neurotransmitters. Recent studies suggest that these agents act through the blockade of specific K+ channels. We have recently identified more potent anthracenone analogs of linopirdine: 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991) and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP 543). Although linopirdine possesses an EC50 of 4.2 microM for enhancement of [3H]ACh release from rat brain slices, XE991 and DMP 543 have EC50S of 490 and 700 nM, respectively. In addition to greater in vitro potency relative to linopirdine, both compounds show greater in vivo potency and duration of action. Although 5 mg/kg (p.o.) linopirdine does not lead to statistically significant increases in hippocampal extracellular acetylcholine levels, 5 mg/kg (p.o.) XE991 leads to increases (maximal effect > 90% over baseline) which are sustained for 60 min. Moreover, DMP 543 at 1 mg/kg causes more than a 100% increase in acetylcholine levels with the effect lasting more than 3 hr. At doses relevant to their release-enhancing properties, the only overt symptom consistently observed was tremor, possible via a cholinergic mechanism. These results suggest that XE991 and DMP 543 may prove to be superior to linopirdine as Alzheimer's disease therapeutics. In addition, these agents should be useful pharmacological tools for probing the importance of particular ion channels in the control of neurotransmitter release.

XE 991 dihydrochloride, a Kv7 (KCNQ) channels blocker, potently inhibits Kv7.1 (KCNQ1), Kv7.2 (KCNQ2), Kv7.2 + Kv7.3 (KCNQ3) channel, and M-current with IC50s of 0.75 µM, 0.71 µM, 0.6 μM, and 0.98 µM, respectively.

XE 991 dihydrochloride,122955-13-9,Natural Products,Potassium Channel, buy XE 991 dihydrochloride , XE 991 dihydrochloride supplier , purchase XE 991 dihydrochloride , XE 991 dihydrochloride cost , XE 991 dihydrochloride manufacturer , order XE 991 dihydrochloride , high purity XE 991 dihydrochloride