Arifhodzic, Lejla; (2001) Novel bis-quinolinium cyclophanes as SKca channel blockers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Small conductance Ca2+ activated K+ channels (SKca) are present in many cells and thought to be involved in some pathophysiological states, including myotonic muscular dystrophy. Some of these channels are potently and selectively blocked by the naturally occurring peptidic toxin apamin, with IC50~1nM. Previous research has led to the discovery of bis-quinolinium cyclophanes as the first nanomolar non-peptidic blockers of the apamin sensitive SKCa channel. The most active compounds discovered were UCL 1684 and UCL 1848, with their structures shown below: [diagram] In order to further explore their activity, we have altered the structure of the two compounds by introducing various substituents at the 6 and 7 positions of their quinoline rings. Whereas all the substituents introduced in UCL 1684 resulted in some loss of potency, the same substituents introduced at the position 6 or 7 of the analogue UCL 1848 seemed to be well tolerated. The influence of the addition of two Cl atoms, at positions 5 and 7 of the two quinoline rings, has also been investigated. Furthermore, changes in the activity caused by varying one or both linkers between the two quinoline rings have been studied. Here, the most interesting finding was that UCL 1684 and UCL 1848 can behave very differently when subjected to the same alteration of one of their linkers. Novel Bis-Quinolinium Cyclophanes as SKCa Channel Blockers It is of great interest to synthesise radioligand for the SkCa channel and by synthesising a series of new compounds we were able to further explore the effect of structure alterations, as well as to produce an iodine containing analogue. Finally, it is uncertain weather the protons attached to the exocyclic N atoms of these cyclophanes can be ionised at physiological pH. In order to explore this aspect, we have attempted the synthesis of structural analogues with more readily ionisable protons. The results obtained in this thesis are supported by molecular modeling studies.

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