Alkoxypsoralens, novel nonpeptide blockers of Shaker-type K+ channels: synthesis and photoreactivity.
A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity 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 normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.
Wulff
H
H
Pharmaceutical Institute and Physiological Institute, University of Kiel, 24118 Kiel, Germany.
Rauer
H
H
Düring
T
T
Hanselmann
C
C
Ruff
K
K
Wrisch
A
A
Grissmer
S
S
Hänsel
W
W
D000818:Animals; D001156:Artemia / Q000187:drug effects / Q000528:radiation effects; D001369:Axons / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004353:Drug Evaluation, Preclinical; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D010100:Oxygen / Q000378:metabolism / Q000528:radiation effects; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011901:Ranvier's Nodes / Q000187:drug effects / Q000648:ultrastructure; D051637:Shaker Superfamily of Potassium Channels; D014466:Ultraviolet Rays; D014982:Xenopus laevis
C115584:5,8-diethoxypsoralen; D003374:Coumarins; D011564:Furocoumarins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051637:Shaker Superfamily of Potassium Channels; D004247:DNA; D010100:Oxygen