|(übersetzt):||Antagonists of the lymphocyte voltage-gated potassium channel Kv1.3 are regarded as a new class of immunosuppressive drugs. In this work new chiral and achiral psoralens have been synthesized and tested for their blocking activity on Kv1.3 by using the patch-clamp technique. Two pairs of enantiomeric psoralens, which have been analyzed by high performance liquid chromatography using a chiral phase, block Kv1.3 without stereospecifity. Several achiral 5-phenylalkoxypsoralens are shown to be highly potent antagonists of Kv1.3 which inhibit the potassium current in the low nanomolar range. A bivalent interaction with the homotetrameric channel is postulated where both the phenyl substituent and the furocoumarin structure bind to the channel protein. Two of these 5-phenylalkoxypsoralens, namely 5-(3-phenylpropoxy)psoralen and 5-(4-phenylbutoxy)psoralen, were further tested for their selectivity against other voltage-gated potassium and sodium channels and for their effects on human T cell proliferation. Altogether, they are the best known nonpeptide blockers of Kv1.3 which could serve as lead structures for the development of a new class of immunosuppressants.
|Schlagworte:||Psoralen ; psoralens, potassium channels, patch clamp, Kv1.3, T lymphocyte, immunosuppression, structure-activity relationship, bivalent ligands