Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca2+-activated K+ channels

Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca2+-activated K+ ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SKCa channel. One of the new compounds (39, R7 = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 54 new analogues have been synthesized and assayed for SK3/SKCa AHP-blocking activity. ► The alkane linker structures in UCL 1848 are optimized for SK3 activity. ► UCL 1848 analogues contain O, S, CF2, CO, CHOH, CC, CHCH or CHMe in place of CH2. ► 25 analogues of UCL 1848 and UCL 1684 contain substituents in the non-N quinolone rings. ► 7 compounds have comparable activity to UCL 1848 and one (39, UCL 2053) is twice as potent.