SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DEQUALINIUM ANALOGSAS K- INVESTIGATIONS ON THE ROLE OF THE CHARGED HETEROCYCLE( CHANNEL BLOCKERS )

Small conductance Ca2+-activated K+ (SKCa) channels occur in many cell s but have been relatively little studied. Dequalinium, a bis-quinolin ium compound, has recently been shown to be the most potent nonpeptidi c blocker of this K+ channel subtype. This paper examines the importan ce of the quinolinium rings for blocking activity. Analogues of dequal inium were synthesised in which one quinolinium group was removed (1 a nd 2) or replaced by a triethylammonium group (3). They have been assa yed in vitro for their ability to block the after-hyperpolarization (m ediated by the opening of SKCa channels) that follows the action poten tial in rat sympathetic neurones. The compound having one quinolinium and one triethylammonium group (3) showed reduced activity, and it is suggested that the stronger binding to the channel of the quinolinium relative to the triethylammonium group may be related to differences i n their electrostatic potential energy maps. Two monoquaternary compou nds (1 and 2) were tested, but they exhibited a different pharmacologi cal profile that did not allow definite conclusions to be drawn concer ning their potency as blockers of the SKCa channel. Replacement of bot h quinolinium groups by pyridinium, acridinium, isoquinolinium, or ben zimidazolium reduced but did not abolish activity. These results show that compounds having a number of different heterocyclic cations are c apable of blocking the SKCa channel. However, among the heterocycles s tudied, quinoline is optimal. Furthermore, charge delocalization seems to be important: the higher the degree of delocalization the more pot ent the compound.