Galanakis, Dimitrios; (1997) Synthesis and structure-activity studies of novel potassium K+ ion channel blockers. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

K+ channels are found in all animal cells where they play a key role in controlling the excitability of the cell. They exist as multiple subtypes most of which have yet to be exploited for therapeutic use. An area in need of pharmacological exploration is that of Ca2+-activated K+ channels. One of the subtypes, the small conductance (apamin-sensitive) Ca2+-activated K+ (SKca) channel is blocked by dequalinium (I, R1= CH3, R2 = NH2, R3= H) at micromolar concentrations. Dequalinium is not adequately potent. Having this as the lead structure, novel analogues of the general type I have been synthesised and submitted for testing for their ability to block the slow after-hyperpolarisation that follows the action potential measured on rat sympathetic neurones. This series was designed to explore whether particular chemical properties of the substituents might affect activity and quantitative structure-activity correlations were sought. Good correlations were obtained between blocking potency and the energies of either of the frontier orbitals (HOMO and LUMO) for the compounds. Furthermore, compounds of the general structure II, where the aminoquinoline rings have been "inverted", have been synthesised and submitted for testing. Again, good correlations were obtained between blocking potency and the energies of either of the frontier orbitals for the compounds. It was also possible to combine the results for both series I and II (i.e. 24 compounds) into a single correlation of potency against the energies of either of the frontier orbitals. Rigidification of the alkyl chain of dequalinium did not alter potency significantly. Furthermore, compounds belonging to series I with R1 = R3 = H, R4 = NH2 having 5, 6, 8, 10 and 12 methylene groups in the alkyl chain had similar activities. The above suggest that the conformational mobility of the alkyl chain as well as the maximum distance between the quinolinium groups are not critical for SKCa channel blockade. Compounds in which the quinolinium groups of dequalinium have been replaced by other charged heterocycles, have also been synthesised and submitted for testing. The aim has been to reveal any special features associated with the quinolinium group. It was shown that compounds with different heterocycles are able to block the SKCa channel but that quinoline was the best heterocycle. Finally, to examine whether both quinolinium groups of dequalinium contribute to SKCa channel blockade and to investigate the nature of their contribution, compound III (having three quinolinium groups) was synthesised and compared with compounds IV and V (having one quinolinium group, previously made) and dequalinium. The affinities of the compounds were determined from inhibition of the specific 125I-apamin binding to SKCa channels of rat brain synaptic plasma membranes. Increasing the number of quinolinium groups increased potency and it is suggested that the contribution of the second and third quinolinium groups in the molecules of dequalinium and III may not be the consequence of direct binding to the channel but may arise from a statistical effect. Compound III is the most potent non-peptidic blocker of the SKCa channel on this assay so far reported.

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