RPR-260243
目录号 : GC32509RPR-260243是HERG钾离子通道激活剂。
Cas No.:668463-35-2
Sample solution is provided at 25 µL, 10mM.
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RPR-260243 is a novel activator of HERG; modifies HERG currents inhibited by dofetilide (IC50 = 58 nM); little effect on HERG current amplitude and no significant effects on steady-state activation parameters or on channel inactivation processes.IC50 value: Target: HERG activatorRPR260243 displayed no activator-like effects on other voltage-dependent ion channels, including the closely related erg3 K+ channel. RPR260243 enhanced the delayed rectifier current in guinea pig myocytes but, when administered alone, had little effect on action potential parameters in these cells. However, RPR260243 completely reversed the action potential-prolonging effects of dofetilide in this preparation. Using the Langendorff heart method, we found that 5 μM RPR260243 increased T-wave amplitude, prolonged the PR interval, and shortened the QT interval. We believe RPR260243 represents the first known HERG channel activator and that the drug works primarily by inhibiting channel closure, leading to a persistent HERG channel current upon repolarization.
[1]. Kang J, et al. Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol. 2005 Mar;67(3):827-36.
Cas No. | 668463-35-2 | SDF | |
Canonical SMILES | O=C([C@H]1CN(CC#CC2=CC(F)=CC(F)=C2F)CC[C@H]1CCC(C3=CC=NC4=CC=C(OC)C=C34)=O)O | ||
分子式 | C28H25F3N2O4 | 分子量 | 510.5 |
溶解度 | DMSO: 10 mg/mL (19.59 mM) | 储存条件 | Store at 2-8°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.9589 mL | 9.7943 mL | 19.5886 mL |
5 mM | 0.3918 mL | 1.9589 mL | 3.9177 mL |
10 mM | 0.1959 mL | 0.9794 mL | 1.9589 mL |
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Concatenated hERG1 tetramers reveal stoichiometry of altered channel gating by RPR-260243
Mol Pharmacol 2015;87(3):401-9.PMID:25519838DOI:10.1124/mol.114.096693.
Activation of human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediates repolarization of action potentials in cardiomyocytes. RPR-260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR) slows deactivation and attenuates inactivation of hERG1 channels. A detailed understanding of the molecular mechanism of hERG1 agonists such as RPR may facilitate the design of more selective and potent compounds for prevention of arrhythmia associated with abnormally prolonged ventricular repolarization. RPR binds to a hydrophobic pocket located between two adjacent hERG1 subunits, and, hence, a homotetrameric channel has four identical RPR binding sites. To investigate the stoichiometry of altered channel gating induced by RPR, we constructed and characterized tetrameric hERG1 concatemers containing a variable number of wild-type subunits and subunits containing a point mutation (L553A) that rendered the channel insensitive to RPR, ostensibly by preventing ligand binding. The slowing of deactivation by RPR was proportional to the number of wild-type subunits incorporated into a concatenated tetrameric channel, and four wild-type subunits were required to achieve maximal slowing of deactivation. In contrast, a single wild-type subunit within a concatenated tetramer was sufficient to achieve half of the maximal RPR-induced shift in the voltage dependence of hERG1 inactivation, and maximal effect was achieved in channels containing three or four wild-type subunits. Together our findings suggest that the allosteric modulation of channel gating involves distinct mechanisms of coupling between drug binding and altered deactivation and inactivation.