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 α 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-pyrrolyl)­methane 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·2HCl] (8) selectively blocked Kv1.1
channels (IC50 ≈ 15 μM) recombinantly expressed
in mammalian cells, induced a positive shift in the voltage dependency
of K+ 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.