Synthesis of psoralen derivatives and their blocking effect of hKv1.5 channel.
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.
Eun
Jae Soon
JS
College of Pharmacy, Woosuk University, Samrye 565-701, Korea.
Kim
Kwang Sik
KS
Kim
Han Na
HN
Park
Seon Ah
SA
Ma
Tian-Ze
TZ
Lee
Kyung A
KA
Kim
Dae Keun
DK
Kim
Hyung Kyo
HK
Kim
In Su
IS
Jung
Young Hoon
YH
Zee
Ok Pyo
OP
Yoo
Dong Jin
DJ
Kwak
Yong Geun
YG
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D005363:Ficusin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection
D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D005363:Ficusin