Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Replacement of this group by other substituents (R4) and quantitative structure-activity relationship (QSAR) analysis on the resultant analogues have yielded a correlation between blocking potency and sigma R for R4 for seven of the compounds. The application of calculated electronic indices enabled the extension of the QSAR to compounds for which the appropriate sigma R values are not available, allowing all 13 analogues of this series to be included in the correlations. Analysis using electronic indices obtained from AM1 MO calculations on model compounds revealed that the blocking potency correlates with the partial charge on the ring N atom, ELUMO, and EHOMO. The EHOMO correlation is qualitatively inconsistent as the HOMO is not the same orbital in all compounds. The ELUMO correlation [pEMR = 1.19(+/- 0.21)ELUMO + 5.41(+/- 1.05), n = 13, r = 0.86, s = 0.274] suggests that the higher the ELUMO the more potent is the analogue. This is consistent with simple charge transfer from the channel to the blocker and may refer to other processes which are important for the strength of the drug-K+ channel interaction such as the desolvation of the compounds.