• Bulletin of the Korean Chemical Society
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• v.32 no.1
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• pp.251-262
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• 2011

Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : $r^2$ = 0.955, $q^2$ = 0.781, $r^2_{pred}$ = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.5
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• pp.305-310
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• 2010

The human $ether$-$a$-$go$-$go$-related gene ($hERG$) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the effects of two antipsychotics, tiapride and sulpiride, on hERG channels expressed in $Xenopus$ oocytes and also on delayed rectifier $K^+$ currents in guinea pig cardiomyocytes. Neither the amplitude of the hERG outward currents measured at the end of the voltage pulse, nor the amplitude of hERG tail currents, showed any concentration-dependent changes with either tiapride or sulpiride ($3{\sim}300{\mu}M$). However, our findings did show that tiapride increased the potential for half-maximal activation ($V_{1/2}$) of HERG at $10{\sim}300{\mu}M$, whereas sulpiride increased the maximum conductance ($G_{max}$) at 3, 10 and $100{\mu}M$. In guinea pig ventricular myocytes, bath applications of 100 and $500{\mu}M$ tiapride at $36^{\circ}C$ blocked rapidly activating delayed rectifier $K^+$ current ($I_{Kr}$) by 40.3% and 70.0%, respectively. Also, sulpiride at 100 and $500{\mu}M$ blocked $I_{Kr}$ by 38.9% and 76.5%, respectively. However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier $K^+$ current ($I_{Ks}$) at the same concentrations. Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of IKr are well above the reported therapeutic plasma concentrations of free and total compound.

• Journal of the Korean Magnetics Society
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• v.7 no.3
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• pp.129-133
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• 1997

To investigate the influence of the Hf concentration and the annealing effect in $Co_{1-x}Hf_x$(X=0.16, 0.24 at.%) systems, ferromagnetic resonance experiments have been carried out. Spin wave resonance spectra for all samples consist of several volume modes and one (or two) surface mode. It is suggested that both surfaces of the film have a perpendicular hard axis to the film plane (negative surface anisotropy). The surface anisotropy $K_{s2}$ at substrate-film interface is varied slowly from -0.07 to -0.32 erg/$\textrm{cm}^2$ and the surface anisotropy $K_{s1}$ at film-air interface is varied from 0.18 to -0.47 erg/ $\textrm{cm}^2$ with increasing annealing temperature in the amorphous $Co_{84}Hf_{16}$ thin films. Also, the surface anisotropy $K_{s2}$ is varied slowly from -0.31 to -0.41 erg/$\textrm{cm}^2$ and the surface anisotropy $K_{s1}$is varied from -0.19 to -0.60 erg/$\textrm{cm}^2$ with increasing annealing temperature in the amporphous $Co_{84}Hf_{16}$ thin films. We conjecture that the variation of surface anisotropy $K_{s1}$ is due to the increase of Co concentration resulted from Hf oxidation for low temperature annealing(150~175 $^{\circ}C$) and the diffusion of Co atoms near the film surfaces for high temperature annealing (200~225 $^{\circ}C$).

• Environmental Engineering Research
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• v.24 no.2
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• pp.254-262
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• 2019

The impact of free cyanide ($CN^-$) and thiocyanate ($SCN^-$) on the $CN^-$ (CDO) and $SCN^-$ degraders (TDO) to nitrify and denitrify aerobically was evaluated under alkaline conditions. The CDO's were able to nitrify under cyanogenic conditions, achieving $NH_4{^+}-N$ removal rates above 1.66 mg $NH_4{^+}-N.L^{-1}.h^{-1}$, except when $CN^-$ and $SCN^-$ loading was 15 mg $CN^-/L$ and 50 mg $SCN^-.L^{-1}$, respectively, which slightly inhibited nitrification. The TDO's were able to achieve a nitrification rate of 1.59 mg $NH_4{^+}-N.L^{-1}.h^{-1}$ in the absence of both $CN^-$ and $SCN^-$, while the presence of $CN^-$ and $SCN^-$ was inhibitory, with a nitrification rates of 1.14 mg $NH_4{^+}-N.L^{-1}.h^{-1}$. The CDO's and TDO's were able to denitrify aerobically, with the CDO's obtaining $NO_3{^-}-N$ removal rates above 0.67 mg $NO_3{^-}-N.L^{-1}.h^{-1}$, irrespective of the tested $CN^-$ and $SCN^-$ concentration range. Denitrification by the TDO's was inhibited by $CN^-$, achieving a removal rate of 0.46 mg $NO_3{^-}-N.L^{-1}.h^{-1}$ and 0.22 mg $NO_3{^-}-N.L^{-1}.h^{-1}$ when $CN^-$ concentration was 10 and 15 mg $CN^-.L^{-1}$, respectively. However, when the CDO's and TDO's were co-cultured, the nitrification and aerobic denitrification removal rates were 1.78 mg $NH_4{^+}-N.L^{-1}.h^{-1}$ and 0.63 mg $NO_3{^-}-N.L^{-1}.h^{-1}$ irrespective of $CN^-$ and $SCN^-$ concentrations.

• Proceedings of the IEEK Conference
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• 2000.07b
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• pp.637-640
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• 2000

ERG signal represents the responses of the each layer of retina for the visual stimulus and accumulated responses according to the signal processing occurring in the retina. By investigating the reaction types of each wave of the ERG, various kinds of information for the diagnosis and the signal processing mechanisms in the retina can be obtained. In this paper, the ERG signal is generated by simulating of the volume conductor field of response of each retina layer and summing of them algebraically. The retina model used for simulation is Shah’s Computer Retina model which is one of the most reliable models recently developed. The generated ERG is compared with the typical ERG and shows a very close similarity. By changing the parameters of the retina model, the diagnostic investigation is performed with the variation of the ERG waveform.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.77.1-77.1
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• 2003

Prolongation of the QT interval may result in a potentially dangerous arrhythmia. The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\sub$Kr). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on human ether-a go-go-related gene (hERG) channels expressed in CHO cells, known to be equal to I$\sub$kr/. We have transfected JERG into CHO cell lines transiently to express high levels of functional hERG channels. (omitted)

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.90.3-91
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• 2003

The most commonly proposed mechanism for QT interval prolongation(LQT) by pharmaceuticals is inhibition of the rapid delayed rectifier potassium channel (I$\_$Kr/). The LQT potency of pharmaceuticals can be effectively evaluated by examining the effect on hERG channels expressed in CHO cells, known to be equal to I$\_$Kr/. But, It was known that hERG channels according to increase the bath temperature have several changes, including a marked increase in the amplitude of the outward and tail currents, and acceleration of the rates of activation, recovery from inactivation, and deactivation. (omitted)

• Journal of Ginseng Research
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• v.46 no.5
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• pp.683-689
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• 2022

Background: Since ginsenosides exert an anti-thrombotic activity, blood flow-improving effects of DK-MGAR101, an extract of mountain ginseng adventitious roots (MGAR) containing various ginsenosides, were investigated in comparison with an extract of Korean Red Ginseng (ERG). Methods: In Sprague-Dawley rats orally administered with DK-MGAR101 or ERG, oxidative carotid arterial thrombosis was induced with FeCl₃ (35%), and their blood flow and occlusion time were measured. To elucidate underlying mechanisms, the cytoprotective activities on rat aortic endothelial cells (RAOECs) exposed to hydrogen peroxide (H₂O₂) were confirmed. In addition, the inhibitory activities of DK-MGAR101 and ERG on agonist-induced platelet aggregation, thromboxane B₂ production, and ATP granule release from stimulated platelets as well as blood coagulation were analyzed. Results: DK-MGAR101 containing high concentrations of Rb1, Rg1, Rg3, Rg5, and Rk1 ginsenosides (55.07 mg/g) was more effective than ERG (ginsenosides 8.45 mg/g) in protecting RAOECs against H₂O₂ cytotoxicity. DK-MGAR101 was superior to ERG not only in suppressing platelet aggregation, thromboxane B₂ production, and granule release, but also in delaying blood coagulation, FeCl₃-induced arterial occlusion, and thrombus formation. Conclusions: The results indicate that DK-MGAR101 prevents blood vessel occlusion by suppressing platelet aggregation, thrombosis, and blood coagulation, in addition to endothelial cell injury.

• Reproductive and Developmental Biology
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• v.34 no.3
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• pp.153-159
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• 2010

The 34 potently pig pheromonal odorants (1-32, 5755 & 7113) through structure-based virtual screening and ligand-based virtual screening method were selected and their ADMET and pharmacokinetics characters were evaluated and discussed quantitatively. The pheromonal odorants were projected on the following pre-calculated models, Caco-2 cell permeability, blood-brain barrier permeation, hERG inhibition and volume-distribution. From the results of in silico study, it is found that an optimal compound (31) either penetrating or have a little ($P_{caco2}$=-8.143) for Caco-2 cell permeability, moderate penetrating ability ($P_{BBB}$=0.082) for blood-brain barrier permeation, the low QT prolongation ($P_{hERG}$=1.137) for the hERG $K^+$ channel inhibition, and low distribution into tissues ($P_{VD}$=-5.468) for volume-distribution. Therefore, it is predicted that the compound (31) a topical application may be preferable from these based foundings.

• Biomolecules & Therapeutics
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• v.17 no.1
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• pp.1-11
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• 2009

Since the Committee for Proprietary Medicinal Products (CPMP) of the European Union issued in 1997 a "points to consider" document for the assessment of the potential for QT interval prolongation by non-cardiovascular agents to predict drug-induced torsades de pointes (TdP), the QT liability has become the critical safety issue in the development of pharmaceuticals. As TdP is usually linked to delayed cardiac repolarization, international guideline (ICH S7B) has advocated the standard repolarization assays such as in vitro IKr (hERG current) and in vivo QT interval, or in vitro APD (as a follow up) as the best biomarkers for predicting the TdP risk. However, the recent increasing evidence suggests that the currently used above biomarkers and/or assays are not fully predictive for TdP, but also does not address potential new druginduced TdP due to the selective disruption of hERG protein trafficking to the cell membrane or VT and/or VF with QT shortening. There is, therefore, an urgent need for other surrogate markers or assays that can predict the proarrhythmic potential of drug candidate. In this review, we provide an ideal pre-clinical strategy to predict the potentials of QT liability and lethal arrhythmia of the drug candidates with recent issues in this field in mind, not at the expense of discarding therapeutically innovative drugs.