Bis-quinolinium cyclophanes: toward a pharmacophore model for the blockade of apamin-sensitive SKCa channels in sympathetic neurons.

The synthesis, pharmacological evaluation, and molecular modeling studies of unsymmetrical bis-alkylene bis-quinolinium cyclophanes and xylylene-alkylene bis-quinolinium cyclophanes is described. Two important structural features of the pharmacophore for SK(Ca) channel blockade have been identified. These are (i) an optimum distance of ca. 5.8A between the centroids of the pyridinium rings of the two quinolinium groups and (ii) a preference for conformations having the quinolinium groups in a synperiplanar orientation.