Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers

Abstract So far, small conductance Ca 2+ -activated K + channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels ( K i  = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine ( K i  ∼ 30 μM) and similar to the charged compound dequalinium ( K i  = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets.