Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization.