title: Angular methoxy-substituted furo- and pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3.
abstract: The voltage-gated potassium channel Kv1.3 constitutes an attractive target for immunosuppression because of its role in T-lymphocyte activation and its functionally restricted expression to lymphocytes. Blockade of Kv1.3 channels by margatoxin has previously been shown to prevent T-cell activation and attenuate immune responses in vivo. In the present study, several furo- and pyranoquinoline derivatives were synthesized and screened for their blocking activities of Kv1.3 channels, stably expressed in mice-fibroblasts L929. In addition the activities of the compounds on Kv currents of the neuroblastoma cell line N1E-115 were determined. The most potent compounds, the angular furoquinolinone 8-methoxy-2-(1'-methylethyl)-5-methyl-4,5-dihydrofuro[3,2-c]quinolin-4-one (8c) and the angular pyranoquinolinone 9-methoxy-2,2,6-trimethyl-2,6-dihydro-5H-pyrano[3,2-c]quinolin-5-one (9a), inhibited Kv1.3 channels with half-blocking concentrations of 5 and 10 microM, respectively, and displayed 8-fold (8c) and 2-fold (9a) selectivity over Kv currents of N1E-115 cells. Thus, compounds 8c and 9a might function as a template for the development of novel immunosuppressants.
authors: Pharmaceutical Institute, University of Kiel, Gutenbergstrasse 76, 24118 Kiel, Germany. ibutenschoen@pharmazie.uni-kiel.de
authors: I
authors: I
authors: Butenschön
authors: K
authors: K
authors: Möller
authors: W
authors: W
authors: Hänsel
mesh_terms: D000818:Animals; D002460:Cell Line; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051664:Kv1.3 Potassium Channel; D051379:Mice; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D026941:Sodium Channel Blockers; D013329:Structure-Activity Relationship
chemical_list: C424982:8-methoxy-2-(1'-methylethyl)-5-methyl-4,5-dihydrofuro(3,2-c)quinolin-4-one; C425230:9-methoxy-2,2,6-trimethyl-2,6-dihydro-5H-pyrrano(3,2-c)quinolin-5-one; D005663:Furans; D007166:Immunosuppressive Agents; C496974:Kcna3 protein, mouse; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines; D015363:Quinolones; D026941:Sodium Channel Blockers