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On the Concept of a Bivalent Pharmacophore for SK Ca Channel Blockers: Synthesis, Pharmacological Testing, and Radioligand Binding Studies on Mono‐, Bis‐, and Tris‐quinolinium Compounds
Author(s) -
Galanakis Dimitrios,
Ganellin C. Robin,
Dunn Philip M.,
Jenkinson Donald H.
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963291203
Subject(s) - chemistry , apamin , radioligand , dissociation constant , stereochemistry , potency , radioligand assay , channel blocker , binding site , biophysics , receptor , biochemistry , in vitro , organic chemistry , calcium , biology
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 [ 125 I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b , suggesting that both quinolinium groups are needed for potent and selective SK Ca channel blockade. The trisquinolinium compound 3 (1,1′‐[5‐[4‐(4‐aminoquinolinium‐1‐yl)but‐1‐yl] non‐4‐en‐1,9‐diyl]‐bis‐(4‐aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2 , being the most potent non‐peptidic SK Ca channel blocker reported so far ( K d ∽ 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the „local concentration” of quinolinium groups.