H. Wulff et al., ALKOXYPSORALENS, NOVEL NONPEPTIDE BLOCKERS OF SHAKER-TYPE K- SYNTHESIS AND PHOTOREACTIVITY( CHANNELS ), Journal of medicinal chemistry, 41(23), 1998, pp. 4542-4549
A series of psoralens and structurally related 5,7-disubstituted couma
rins was synthesized and investigated for their K+ channel blocking ac
tivity as well as for their phototoxicity to Artemia salina and their
ability to generate singlet oxygen and to photomodify DNA. After scree
ning the compounds on Ranvier nodes of the toad Xenopus Laevis, the af
finities of the most promising compounds, which proved to be psoralens
bearing alkoxy substituents in the 5-position or alkoxymethyl substit
uents in the neighboring 4- or 4'-position, to a number of homomeric K
+ channels were characterized. All compounds exhibited the highest aff
inity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally
potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity n
ormally inherent in psoralens. The reported compounds represent a nove
l series of nonpeptide blockers of Shaker-type K+ channels that could
be further developed into selective inhibitors of Kv1.2 or Kv1.3.