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Purity: ≥98%
PD-118057 (PD118057) is a novel and potent hERG (Human ether-a-go-go-related gene) channel enhancer. Human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediate repolarization of cardiac action potentials.
| Targets |
hERG channel; Human ether-a-go-go-related gene channel
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|---|---|
| ln Vitro |
PD-118057 (3 μM and 10 μM) specifically enhanced hERG currents and inhibited action potential duration in the ventricular myocardium of acutely isolated guinea pig cardiomyocytes [2-3]. With no change in the "hump" shape of the IKr current recorded by action potential clamp, PD-118057 (10 μM) reversed the current suppression caused by Dof and Mox and only marginally enhanced the peak value of the suppressed current [3].
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| Enzyme Assay |
IN THIS STUDY, WE INVESTIGATED: (a) the effect of PD-118057 and thapsigargin on the current amplitudes of WT-hERG and WT/E637K-hERG channels; (b) the effect of PD-118057 and thapsigargin on the biophysical properties of WT-hERG and WT/E637K-hERG channels; (c) whether drug treatment can rescue channel processing and trafficking defects of the WT/E637K-hERG mutant.
Methods: The whole-cell Patch-clamp technique was used to assess the effect of PD-118057 and thapsigargin on the electrophysiological characteristics of the rapidly activating delayed rectifier K(+) current (Ikr) of the hERG protein channel. Western blot was done to investigate pharmacological rescue on hERG protein channel function.
Results: In our study, PD-118057 was shown to significantly enhance both the maximum current amplitude and tail current amplitude, but did not alter the gating and kinetic properties of the WT-hERG channel, with the exception of accelerating steady-state inactivation. Additionally, thapsigargin shows a similar result as PD-118057 for the WT-hERG channel, but with the exception of attenuating steady-state inactivation. However, for the WT/E637K-hERG channel, PD-118057 had no effect on either the current or on the gating and kinetic properties. Furthermore, thapsigargin treatment did not alter the current or the gating and kinetic properties of the WT/E637K-hERG channel, with the exception of opening at more positive voltages.
Conclusion: Our findings illustrate that neither PD-118057 nor thapsigargin play a role in correcting the dominant-negative effect of the E637K-hERG mutant[1].
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| Cell Assay |
Cell Lines and Drug Exposure[1]
Human embryonic kidney 293 (HEK293) cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum in 5% CO2 incubator at 37°C. HEK293 cells were transiently transfected with 3.2 µg of WT-hERG and/or 3.2 µg of E637K-hERG plasmids using Lipofectamine™ 2000 according to the manufacturer’s instruction. 0.8 µg of pRK5-GFP plasmid was co-transfected to monitor transfection efficacy. Thapsigargin (1 mmol/L stock dissolved in DMSO), PD-118057 (5 mmol/L stock dissolved in DMSO) were added to the culture media for different time periods before analyzing. Final DMSO concentrations in medium was <0.1%.Incubating HEK293 cells expressing WT-hERG, WT/E637K-hERG or E637K-hERG overnight in 0.1% DMSO had no effect on IhERG or complex glycosylation. |
| References |
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| Additional Infomation |
Previous studies have shown that murine portal vein myocytes express ether-à-go-go related genes (ERGs) and exhibit distinctive currents when recorded under symmetrical K(+) conditions. The aim of the present study was to characterize ERG channel currents evoked from a negative holding potential under conditions more pertinent to a physiological scenario to assess the possible functional impact of this conductance. Currents were recorded with ruptured or perforated patch variants of the whole cell technique from a holding potential of -60 mV. Application of three structurally distinct and selective ERG channel blockers, E-4031, dofetilide, and the peptide toxin BeKM-1, all inhibited a significant proportion of the outward current and abolished inward currents with distinctive "hooked" kinetics recorded on repolarization. Dofetilide-sensitive currents at negative potentials evoked by depolarization to +40 mV had a voltage-dependent time to peak and rate of decay characteristic of ERG channels. Application of the novel ERG channel activator PD-118057 (1-10 microM) markedly enhanced the hooked inward currents evoked by membrane depolarization and hyperpolarized the resting membrane potential recorded by current clamp and the perforated patch configuration by approximately 20 mV. In contrast, ERG channel blockade by dofetilide (1 microM) depolarized the resting membrane potential by approximately 8 mV. These data are the first record of ERG channel currents in smooth muscle cells under quasi-physiological conditions that suggest that ERG channels contribute to the resting membrane potential in these cells.[2]
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| Molecular Formula |
C21H17CL2NO2
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|---|---|
| Molecular Weight |
386.271183729172
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| Exact Mass |
385.064
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| Elemental Analysis |
C, 65.30; H, 4.44; Cl, 18.35; N, 3.63; O, 8.28
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| CAS # |
313674-97-4
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| PubChem CID |
9864959
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.353g/cm3
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| Boiling Point |
527ºC at 760 mmHg
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| Flash Point |
272.52ºC
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| Index of Refraction |
1.668
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| LogP |
6.293
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
453
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZCQOSCDABPVAFB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H17Cl2NO2/c22-18-12-9-15(13-19(18)23)6-5-14-7-10-16(11-8-14)24-20-4-2-1-3-17(20)21(25)26/h1-4,7-13,24H,5-6H2,(H,25,26)
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| Chemical Name |
2-[4-[2-(3,4-Dichlorophenyl)ethyl]anilino]benzoic acid
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| Synonyms |
PD118057; PD-118057; PD-118057; 313674-97-4; 2-[[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]amino]benzoic acid; 2-[4-[2-(3,4-dichlorophenyl)ethyl]anilino]benzoic acid; 2-((4-(3,4-dichlorophenethyl)phenyl)amino)benzoic acid; 2-({4-[2-(3,4-DICHLOROPHENYL)ETHYL]PHENYL}AMINO)BENZOIC ACID; ZCQOSCDABPVAFB-UHFFFAOYSA-N; PD 118057
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~258.89 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5889 mL | 12.9443 mL | 25.8886 mL | |
| 5 mM | 0.5178 mL | 2.5889 mL | 5.1777 mL | |
| 10 mM | 0.2589 mL | 1.2944 mL | 2.5889 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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