Fletcher, David Ian; (1997) Synthesis and structure-activity studies of novel potassium ion channel blockers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Small conductance Ca2+ activated potassium channels (SKCa) occur in many cells but, until recently, have been relatively little studied. Interest in this field has been generated by the discovery of agents which selectively block the channel, notably several insect and anthropod toxins with high potency, and a variety of smaller molecules, the most active of which is dequalinium. This thesis describes the synthesis of novel compounds as potential blocking agents of the SKCa channel, in order to examine the nature of the interaction with the channel protein, and in particular to identify any structural features additional to the two arginine residues in the peptide toxins which have been proposed to participate in binding. Each compound was assayed in vitro for its ability to block the after-hyperpolarisation (mediated by the opening of the SKCa channels) that follows the action potential in rat sympathetic neurones. An initial series of compounds was prepared comprising various elaborations on a fumaric acid-based bis-guanidinium compound, which had possessed weak activity. Incorporation of an additional aminoalkyl substituent resulted in a significant increase in potency. Replacement of the guanidine groups in this compound by 4-aminoquinoline increased the activity 100 fold to a level greater than dequalinium. A variety of derivatives where three and four aminoquinolinyl groups are attached by alkyl chains to a meta-substituted aromatic central unit was also prepared, based on a 1,6- disubstituted indane as a mimic for an a-helix. All were found to be more potent than dequalinium. The relative potencies are discussed in terms of the energy changes of the binding process, and it is concluded that only two of the electropositive groups interact with the channel protein. A proposal for their relative spatial relationship is discussed, and is consistent with current hypotheses concerning the dependence on charge delocalisation, and the involvement of a hydrophobic contribution, probably operating at short range, in addition to the primary electrostatic interaction of two charged groups separated by approximately 11 A. Quaternisation of the basic residues is unnecessary, provided that the groups are protonated at physiological pH; the linkage position of the chains through the exocyclic or endocyclic nitrogen of each aminoquinoline is also not critical.

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