Synthesis of psoralen derivatives and their blocking effect of hKv1.5 channel

Abstract

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.

Downregulation of Kv1.5 K+Channels by the AMP-Activated Protein Kinase

“…Kv1.5 is highly expressed in atrial myocytes [21] and loss-of-function Kv1.5 mutations may cause atrial fibrillation [22]. Kv1.5 is thus an attractive target for the treatment of atrial arrhythmias [13,[23][24][25][26][27][28][29][30][31][32]. Kv1.5 is further expressed in several tumor cells and participates in the regulation of adhesion, proliferation and sensitivity to apoptosis [33][34][35][36][37][38][39].…”

Effect of psoralen on the cloned Kv3.1 currents

“…It is widely used in the treatment of psoriasis (Scott et al, 1976), cancer (Fossell et al, 1991;Young, 1993) and arthritis (Malawista et al, 1991). Recently, effects of psoralen on ion channels were reported (Vennekamp et al, 2004;Eun et al, 2005;Eun et al, 2007;Pereira et al, 2007).…”

Decursin from Angelica gigas Nakai Blocks hKv1.5 Channel

“…This suggests that decursin acts as an open channel blocker on the hKv1.5 channel. On the basis of all these results, we suggest that decursin blocks hKv1.5 currents not by its known-mechanism, but rather via a direct one-to-one interaction between the drug and the channel in the open state, like as papaverine (Choe et al, 2003), oxypeucedanin (Eun et al, 2005b), psoralen (Eun et al, 2005a;Eun et al, 2007) and torilin (Kwak et al, 2006). The use-dependence of decursin-induced inhibition of the hKv1.5 channel was investigated.…”

“…Our studies have focused on the development of antiarrhythmic drug, and we previously reported that papaverine (Choe et al, 2003), oxypeucedanin (Eun et al, 2005b), psoralen and their derivatives (Eun at al., 2005a;Eun et al, 2007) and torilin (Kwak et al, 2006) inhibited the hKv1.5 current. The present study was examined to investigate the effect of decursin from A. gigas on hKv1.5 channels using the whole-cell patch-clamp technique.…”