A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction.

K+ channels containing Kv1.1 alpha subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K+ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyeinethane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'-carbonyl)bis(azanediyl)) diethaneamine center dot 2HCl] (8) selectively blocked Kv1.1 channels (IC50 approximate to 15 mu M) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K4 current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.