Blocking of potassium channels in Ranvier nodes by 1,2,3,4,10-substituted acridin-9-ons and its possible significance on demyelinating diseases.

Demyelinating diseases like multiple sclerosis (MS) uncover internodal potassium channels in myelinated axons (Chiu and Ritchie 1982), thus rendering impulse propagation difficult (Waxman 1987). Therefore, the role of potassium channel blockers like 4-aminopyridine (Stefoski et al. 1991; van Diemen et al. 1991) and substituted benzofurans (Bohuslavizki et al. 1993) in the symptomatic treatment of MS recently received much attention. In the search for further potassium channel blockers of therapeutical use in de-myelinating diseases we discovered 1,2,3,4,10-substituted acridin-9-ons (=acridons) of the general structure outlined in Figure 1. Various compounds (see Table 1) were tested on isolated intact myelinated nerve fibres of the toad Xenopus laevis using the potential clamp technique (Bethge et al. 1991). The experiments were carried out both under normal external potassium concentration (Ringer solution) and under high potassium concentration (for the respective ionic concentrations see Bohuslavizki et al. 1993). Test solutions were prepared immediately before use by dissolving the compound to be tested in dimethyl sulfoxide (DMSO; 99,96%); dilution by the corresponding bathing medium gave the final concentrations of the drug and the solvent of 50 to 100 /imol/1 and 700 mmol/1, respectively. Both onset and in particular washout of the effects of the tested acridons took decisively more time than the corresponding effects of benzofurans (Bohuslavizki et al. 1993). In general, after about 10 min the observed changes were fully reversible. Test pulses were preceded by constant hyperpolarizing prepulses, thus the sodium inactivation variable, h, was unity (Frankenhaeuser 1959) except for experiments concerning the potential dependence of h, i.e. the so-called inactivation curve, where pre-pulses were varied instead of test pulses.