title: On the concept of a bivalent pharmacophore for SKCa channel blockers: synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds.
abstract: The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]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 SKCa 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 SKCa channel blocker reported so far (Kd approximately 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.
authors.affiliation: University College London, Department of Chemistry, Christopher Ingold Laboratories, U.K.
authors.forename: D
authors.initials: D
authors.lastname: Galanakis
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: P M
authors.initials: PM
authors.lastname: Dunn
authors.forename: D H
authors.initials: DH
authors.lastname: Jenkinson
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers; D004337:Drug Carriers; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011806:Quinolinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D004337:Drug Carriers; D011806:Quinolinium Compounds