Inhibition of hEAG1 and hERG1 potassium channels by clofilium and its tertiary analogue LY97241

Abstract

1 We investigated the inhibition of hEAG1 potassium channels, expressed in mammalian cells and Xenopus oocytes, by several blockers that have previously been reported to be blockers of hERG1 channels. 2 In the whole-cell mode of mammalian cells, LY97241 was shown to be a potent inhibitor of both hEAG1 and hERG1 channels (IC 50 of 4.9 and 2.2 nM, respectively). Clo®lium, E4031, and haloperidol apparently inhibited hEAG1 channels with lower potency than hERG1 channels, but they cannot be considered hERG1-speci®c. 3 The block of hEAG1 channels by LY97241 and clo®lium was time-, use-, and voltage-dependent, best explained by an open-channel block mechanism. 4 Both drugs apparently bind from the intracellular side of the membrane at (a) speci®c site(s) within the central cavity of the channel pore. They can be trapped by closure of the activation gate. 5 In inside-out patches from Xenopus oocytes, hEAG1 block by clo®lium was stronger than by LY97241 (IC 50 of 0.8 and 1.9 nM, respectively). In addition, hEAG1 block by clo®lium was much faster than by LY97241 although there was no di erence in the voltage dependence of the on-rate of block. 6 Physico-chemical di erences of clo®lium and the weak base LY97241 determine the access of the drugs to the binding site and thereby the in¯uence of the recording mode on the apparent block potencies. This phenomenon must be considered when assessing the inhibitory action of drugs on ion channels.

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

“…We determined that cell proliferation, measured as number of viable cells after a given period of time, is decreased by TEA at submillimolar concentration (a drug concentration that blocks MaxiK, Kv1.1, Kv3 and Kv7.2 channels [49,50]) and by micromolar concentration of clofilium (concentration effective to block HERG channels [51]). Significantly, we have previously shown that similar concentrations of TEA and clofilium inhibited I r and I s , respectively [18].…”

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

“…The tertiary central nitrogen on ibutilide allows the compound to exist in a neutral or protonated (positively charged) state at physiological pH. By contrast, the quaternary central nitrogen on clofilium carries permanent positive charge that confers low lipid permeability and is thought to be responsible for its slow equilibration across the plasma membrane and slow kinetics for hERG block (Castle 1991;Gessner and Heinemann, 2003). To determine whether the extra ethyl group on the central nitrogen (and permanent positive charge) is responsible for the distinct kinetics and/or binding of clofilium, we compared block by a tertiary analog PNU-0068611A (structures given in Fig.…”

“…at ASPET Journals on May 10, 2018 molpharm.aspetjournals.org measure because of the extraordinarily slow time course for onset of block with low (Ͻ 100 nM) concentrations (Gessner and Heinemann, 2003;Perry et al, 2004). Percentage block with 300 nM was slightly greater for the quaternary than tertiary compound.…”

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

“…Preliminarily, we examined the expression of Kir 2.1, herg1, helk2 and heag transcripts in both cell lines. hEAG was included in the screen because it is expressed in human primary gliomas (Patt et al, 2004), and because hERG channel inhibitors also block hEAG currents at high concentrations (Gessner and Heinemann, 2003;Gessner et al, 2004).…”