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Synthesis of Psoralen Derivatives and Their Blocking Effect of hKv1.5 Channel
은재순,김광식,김한나,박선아,Tian-Ze Ma,이경아,김대근,김형교,김인수,정영훈,지옥표,유동진,곽용근 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2
Previously, we found that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-7- one), blocked a human Kv1.5 potassium channel (hKv1.5) and has a potential antiarrhythmic effect. In the present study, to develop more potent hKv1.5 blockers or antiarrhythmic drugs, we synthesized ten psoralen derivatives and examined their blocking effects on hKv1.5 stably expressed in Ltk- cells. Among the newly synthesized psoralen derivatives, three derivatives (Compounds 5, 9 and 10) showed the open channel-blocking effect. Compound 9 among them was the most potent in blocking hKv1.5. We found that compound 9, one of the psoralen derivatives, inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent manner with an IC50 value of 27.4 ± 5.1 nM at +60 mV. Compound 9 accelerated the inactivation kinetics of the hKv1.5 channel, slowed the deactivation kinetics of hKv1.5 current resulting in a tail crossover phenomenon. Compound 9 inhibited hKv1.5 current in a use-dependent manner. These results indicate that compound 9, one of psoralen derivatives, acts on hKv1.5 channel as an open channel blocker and is much more potent than psoralen in blocking hKv1.5 channel. If further studies were done, compound 9 might be an ideal antiarrhythmic drug for atrial fibrillation.
Synthesis of Psoralen Derivatives and Their Blocking Effect of hKv1.5 Channel
Eun, Jae-Soon,Kim, Kwang-Sik,Kim, Han-Na,Park, Seon-Ah,Ma, Tian-Ze,Lee, Kyung-A,Kim, Dae-Keun,Kim, Hyung-Kyo,Kim, In-Su,Jung, Young-Hoon,Zee, Ok-Pyo,Yoo, Dong-Jin,Kwak, Yong-Geun 대한약학회 2007 Archives of Pharmacal Research Vol.30 No.2
Previously, we found that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1 ]benzopyran-7-one), blocked a human Kv1.5 potassium channel (hKv1.5) and has a potential antiarrhythmic effect. In the present study, to develop more potent hKv1.5 blockers or antiarrhythmic drugs, we synthesized ten psoralen derivatives and examined their blocking effects or hKv1.5 stably expressed in Ltk cells. Among the newly synthesized psoralen derivatives, three derivatives (Compounds 5,9 and 10) showed the open channel-blocking effect. Compound 9 among them was the most potent In blocking hKv1.5. We found that compound 9, one of the psoralen derivatives, inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent manner with an IC$_{50}$ value of 27.4 ${\pm}$ 5.1 nM at +60 mV. Compound 9 accelerated the inactivation kinetics of the hKv1.5 channel, slowed the deactivation kinetics of hKv1.5 current resulting in a tail crossover phenomenon. Compound 9 inhibited hKv1.5 current in a use-dependent manner. These results indicate that compound 9, one of psoralen derivatives, acts on hKv1.5 channel as an open charnel blocker and is much more potent than psoralen in blocking hKv1.5 channel. If further studios were done, compound 9 might be an ideal antiarrhythmic drug for atrial fibrillation.
Lee, Byung-Hwan,Choi, In-Sung,Rhim, Hye-Whon,Choi, Kyung-Il,Nah, Seung-Yeol,Nam, Ghil-Soo Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.11
5-$HT_{3}$ receptor;5-$HT_{3A}$ receptor channel activity;Novel 5-$HT_{3}$ receptor channel current blockers;Chlorophenyl substituted piperazinylethylaminomethylpyrazoles; The 5-$HT_{3A}$ receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-$HT_{3}$ receptor antagonists and evaluated their effects on 5-$HT_{3A}$ receptor channel currents ($I_{5-HT}$) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most of N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e and 7h) exhibited the high potency for the inhibition of $I_{5-HT}$, whereas the compound without chloride (6) or with m-chlorophenyl group (a serious of 8 and 9) showed the low potency. These result indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on $I_{5-HT}$.
Decursin from Angelica gigas Nakai Blocks hKv1.5 Channel
( Dae Keun Kim ),( Yong Geun Kwak ),( Jae Soon Eun ),( Bok Hee Choi ) 한국응용약물학회 2011 Biomolecules & Therapeutics(구 응용약물학회지) Vol.19 No.1
Decursin was purified from Angelica gigas Nakai, and its effects on the human Kv1.5 (hKv1.5) currents were recorded in mouse fibroblasts (Ltk- cells) by whole-cell patch-clamp technique. Decursin inhibited hKv1.5 current in a concentration-dependent manner, with an IC50 value of 2.7 uM at +60 mV. Decursin accelerated the inactivation kinetics of the hKv1.5 channel, and slowed the deactivation kinetics of the hKv1.5 current, resulting in a tail crossover phenomenon. Also, decursin inhibited the hKv1.5 current in a use-dependent manner. These results strongly suggest that decursin is a kind of open-channel blocker of the hKv1.5 channel.
Open Channel Block of hKv1.5 by Psoralen from Heracleum moellendorffii Hance
Jae Soon Eun,Bok Hee Choi,Jeong Ah Park,Ggot Im Lee,Taek Yul Lee,Dae Keun Kim,Young Hoon Jung,유동진,Yong Geun Kwak 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.3
A furocoumarin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-7-one), was isolated from the n-hexane fraction of Heracleum moellendorffii Hance. We examined the effects of psoralen on a human Kv1.5 potassium channel (hKv1.5) cloned from human heart and stably expressed in Ltk- cells. We found that psoralen inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent manner with an IC50 value of 180 ± 21 nM at +60 mV. Psoralen accelerated the inactivation kinetics of the hKv1.5 channel, and it slowed the deactivation kinetics of the hKv1.5 current resulting in a tail crossover phenomenon. These results indicate that psoralen acts on the hKv1.5 channel as an open channel blocker. Furthermore, psoralen prolonged the action potential duration of rat atrial muscles in a dose-dependent manner. Taken together, the present results strongly suggest that psoralen may be an ideal antiarrhythmic drug for atrial fibrillation.
Torilin from Torilis japonica (Houtt.) DC. Blocks hKv1.5 Channel Current
Yong Geun Kwak,김대근,Tian-Ze Ma,박선아,Hoon Park,정영훈,유동진,은재순 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.10
Torilin was purified from Torilis japonica (Houtt.) DC., and its effects on a rapidly activating delayed rectifier K+ channel (hKv1.5), cloned from human heart and stably expressed in Ltk- cells, as well as the corresponding K+ current (the ultrarapid delayed rectifier, IKUR) were assessed in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, torilin was found to inhibit the hKv1.5 current in time and voltage-dependent manners, with an IC50 value of 2.51±0.34 μM at +60 mV. Torilin accelerated the inactivation kinetics of the hKv1.5 channel, and slowed the deactivation kinetics of the hKv1.5 current, resulting in a tail crossover phenomenon. Additionally, torilin inhibited the hKv1.5 current in a usedependent manner. These results strongly suggest that torilin is a type of open-channel blocker of the hKv1.5 channel.
Effects of Oxypeucedanin on hKv1.5 and Action Potential Duration
Eun, Jae Soon,Park, Jung Ah,Choi, Bok Hee,Cho, Sun Kyung,Kim, Dae Keun,Kwak, Yong Geun Pharmaceutical Society of Japan 2005 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.28 No.4
<P>A furocoumarin derivative, oxypeucedanin, was purified from <I>Angelica dahurica</I>, and its effects on the human Kv1.5 (hKv1.5) channel and on the cardiac action potential duration (APD), were examined using the patch-clamp technique and the conventional microelectrode technique. Oxypeucedanin inhibited the hKv1.5 current in a concentration-dependent manner, with an IC<SUB>50</SUB> value of 76 n<SMALL>M</SMALL>, while it had no effect on human eag-related gene (HERG) current. Oxypeucedanin induced an initial fast decline of hKv1.5 current during depolarizations. The inhibition of hKv1.5 channel by oxypeucedanin was voltage-dependent, especially at depolarizing pulses between −40 and 0 mV which corresponds to the voltage range of the channel's opening. Oxypeucedanin also slowed the deactivation time course, resulting in a tail crossover phenomenon. Additionally, oxypeucedanin prolonged the APD of rat atrial and ventricular muscles in a dose-dependent manner. These results suggest that oxypeucedanin is a kind of open-channel blocker of the hKv1.5 channel and it prolongs the APD; therefore, it is an excellent candidate as an antiarrhythmic drug for atrial fibrillation.</P>
Torilin from Torilis japonica (Houtt.) DC. Blocks hKv1.5 Channel Current
Kwak, Yong-Geun,Kim, Dae-Keun,Ma, Tian-Ze,Park, Sun-Ah,Park, Hoon,Jung, Young-Hoon,Yoo, Dong-Jin,Eun, Jae-Soon The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.10
Torilin was purified from Torilis japonica (Houtt.) DC., and its effects on a rapidly activating delayed rectifier $K^+$ channel (hKv1.5), cloned from human heart and stably expressed in Ltk cells, as well as the corresponding $K^+$ current (the ultrarapid delayed rectifier, $I_{KUR}$) were assessed in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, torilin was found to inhibit the hKv1.5 current in time and voltage-dependent manners, with an $IC_50$ value of $2.51{\pm}0.34\;{\mu}M$ at +60 mV. Torilin accelerated the inactivation kinetics of the hKv1.5 channel, and slowed the deactivation kinetics of the hKv1.5 current, resulting in a tail crossover phenomenon. Additionally, torilin inhibited the hKv1.5 current in a use dependent manner. These results strongly suggest that torilin is a type of open-channel blocker of the hKv1.5 channel.
이병환,In Sung Choi,Hyewhon Rhim,Kyung Il Choi,나승열,Ghilsoo Nam 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.11
The 5-HT3A receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-HT3 receptor antagonists and evaluated their effects on 5-HT3A receptor channel currents (I5-HT) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most of N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e and 7h) exhibited the high potency for the inhibition of I5-HT, whereas the compound without chloride (6) or with m-chlorophenyl group (a serious of 8 and 9) showed the low potency. These results indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on I5-HT.