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 it s functionally restricted expression to lymphocytes. Blockade of Kv1.3 chan nels by margatoxin has previously been shown to prevent T-cell activation a nd attenuate immune responses in vivo. In the present study, several furo-a nd pyranoquinoline derivatives were synthesized add screened for their bloc king activities of Kv1.3 channels, stably expressed in mice-fibroblasts L92 9. In addition the activities of the compounds on Ky currents of the neurob lastoma cell line N1E-115 were determined. The most potent compounds, the a ngular furoquinolinone 8-methoxy-2-(1 ' -methylethyl)-5-methyl-4,5-dihydrof uro [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), inhibit ed Kv1.3 channels with half-blocking concentrations of 5 and 10 muM, respec tively, and displayed 8-fold (8c) and 2-fold (9a) selectivity over Ky curre nts of N1E-115 cells. Thus, compounds 8c and 9a might function as a templat e for the development of novel immunosuppressants.