ON THE CONCEPT OF A BIVALENT PHARMACOPHORE FOR SKCA CHANNEL BLOCKERS - SYNTHESIS, PHARMACOLOGICAL TESTING, AND RADIOLIGAND BINDING-STUDIES ON MONO-QUINOLINIUM, BIS-QUINOLINIUM, AND TRIS-QUINOLINIUM COMPOUNDS

The dissociation equilibrium constants (K-d values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [I-125]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the chan nel with 2 orders of magnitude higher affinity than 1a or 1b, suggesti ng that both quinolinium groups are needed for potent and selective SK Ca channel blockade. The trisquinolinium compound 3 -1-yl]non-4-en-1.9 -diyl]-bis-(4-aminoquinolinium)) has been synthesized and tested for i nhibition of the afterhyperpolarization of rat sympathetic neurones an d on the binding assay. Compound 3 shows approximately one order of ma gnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (K-d approximate to 30 nM). The highe r affinity of 3 compared with 2 may be due to direct binding of the th ird quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the ''local conc entration'' of quinolinium groups.