Angular methoxy-substituted furo- and pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3

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 add screened for their blocking activities of Kv1.3 channels, stably expressed in mice-fibroblasts L929. In addition the activities of the compounds on Ky 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 muM, respectively, and displayed 8-fold (8c) and 2-fold (9a) selectivity over Ky currents of N1E-115 cells. Thus, compounds 8c and 9a might function as a template for the development of novel immunosuppressants.