Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca(2+)-activated K+ channels.

Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca(2+)-activated K(+) ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SKCa channel. One of the new compounds (39, R(7) = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.

Synthesis and pharmacological testing of polyaminoquinolines as blockers of the apamin-sensitive Ca2+-activated K+ channel (SK(Ca)).

The synthesis and pharmacological testing of a series of non-peptidic blockers of the SK(Ca) (SK-3) channel is described. Target compounds were designed to mimic the spatial relationships of selected key residues in the energy-minimised structure of the octadecapeptide apamin, which are a highly potent blocker of this channel. Structures consist of a central unit, either a fumaric acid or an aromatic ring, to which are attached two alkylguanidine or two to four alkylaminoquinoline substituents. Potency was tested by the ability to inhibit the SK(Ca) channel-mediated after-hyperpolarization (AHP) in cultured rat sympathetic neurones. It was found that bis-aminoquinoline derivatives are significantly more potent as channel blockers than are the corresponding guanidines. This adds to the earlier evidence that delocalisation of positive charge through the more extensive aminoquinolinium ring system is important for effective channel binding. It was also found that an increase in activity can be gained by the addition of a third aminoquinoline residue to give non-quaternized amines which have submicromolar potencies (IC(50)=0.13-0.36 microM). Extension to four aminoquinoline residues increased the potency to IC(50)=93 nM.

Potassium channels--multiplicity and challenges.

The development of our knowledge of the function, structure and pharmacology of K(+) channels is briefly outlined. This is the most diverse of all the ion channel families with at least 75 coding genes in mammals. Alternative splicing as well as variations in the channel subunits and accessory proteins that co-assemble to form the functional channel add to the multiplicity. Whereas diversity of this order suggests that it may be possible to develop new classes of drug, for example, for immunomodulation and some diseases of the central nervous system, the ubiquity of K(+) channels imposes stringent requirements for selectivity. Animal toxins from the snake, bee and scorpion provide useful leads, though only in a few instances (e.g. with apamin) it has been possible to produce non-peptidic analogues of high potency. The scale of the resources needed to identify, and characterize fully, specific K(+) channel as targets and then develop modulators with the required selectivity presents a challenge to both academic and applied pharmacologists.