Dissertation (Metadaten)
Titel:Synthese und elektrophysiologische Testung hochwirksamer Psoralenderivate als nicht-peptidische Blocker des lymphozytären Kaliumkanals Kv1.3
 
Autor:Julia Vennekamp
 
URN:NBN:urn:nbn:de:gbv:8-diss-6452
 
Fakultät:Mathematisch-Naturwissenschaftliche Fakultät
DDC Sachgebiet:610 Medizin und Gesundheit
 
Datum der mdl. Prüfung:06.11.2002
 
Referent(in):Prof. Dr. W. Hänsel
Korreferent(en) Korreferentin:Prof. Dr. S. Grissmer, Ulm
 
Beschreibung (original):(Keine Zusammenfassung in deutscher Sprache vorhanden.) (No summary in German language.)
 
(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
 
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