Targeting the Kv11.1 (hERG) channel with allosteric modulators. Synthesis and biological evaluation of three novel series of LUF7346 derivatives

We synthesized and evaluated three novel series of substituted benzophenones for their allosteric modulation the human K v 11.1 (hERG) channel. compared effects with reference compound LUF7346 previously shown to shorten action potential cardiomyocytes derived from stem cells. Most compounds behaved as negative modulators (NAMs) [ 3 H]dofetilide binding Compound 9i was most potent amongst all ligands, remarkably reducing affinity dofetilide in competitive displacement assays. One other derivatives ( 6k ) tested a second radioligand set-up, displayed unusual characteristics pseudo-Hill coefficient significantly distinct unity, further indicative its on Some were more physiologically relevant context beating induced pluripotent Surprisingly, showed quite different NAM LUF7346. For instance, 5e prolonged, rather than shortened, field duration, while it did not influence this parameter when already prolonged by dofetilide. In subsequent patch clamp studies HEK293 cells expressing hERG channel blockers. conclusion, we successfully identified new Unexpectedly, differed functional assays hERG-HEK293 cardiomyocytes, extent that stand-alone Novel channel? • Three synthesized, based Potent identified. Divergent elicited Emerging blockers electrophysiological studies.