SYNTHESIS, MOLECULAR MODELING, AND K-BLOCKING ACTIVITY OF DEQUALINIUMANALOGS HAVING SEMIRIGID LINKERS( CHANNEL)

Dequalinium decane-1,10-diyl)bis(2-methyl-4-aminoquinolinium)] is an e ffective blocker of the small conductance Ca2+-activated K+ channel. I t has been shown that the number of methylene groups in the alkyl chai n linking the two quinolinium rings of this type of molecule is not cr itical for activity. To further investigate the role of the linker, an alogues of dequalinium have been synthesized, in which the alkyl chain has been replaced by CH(2)XCH(2) where X is a rigid or semirigid grou p containing aromatic rings. The compounds have been tested for blocka de of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)(n)C6H4, where n = 0-4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeli ng system. Although there is some dependence of the potency of the ana logue on the conformational properties of the linker (X), overall, X g roups having substantial structural differences are tolerated. It seem s that X provides a support for the two quinolinium groups and does no t interact with the channel directly. The intramolecular separation be tween the quinolinium rings, which is provided by rigid groups X, is n ot critical for activity; this may be attributed to the residual confo rmational mobility of the heterocycles and to the extensive delocaliza tion of the positive charge. These two factors may permit favorable co ntacts between the quinolinium groups and the channel over a range of intramolecular separations.