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.

Selective inhibitors of voltage-activated K+ channels are needed for the treatment of multiple sclerosis. In this work it was discovered that porphyrins bearing 2–4 carbon alkyl ammonium side chains predominantly blocked the Kv1.1 current whilst Kv1.2 was susceptible to a porphyrin bearing polyamine side chains.

Selective inhibitors of voltage-activated K+ channels are needed for the treatment of multiple sclerosis. In this work it was discovered that porphyrins bearing 2–4 carbon alkyl ammonium side chains predominantly blocked the Kv1.1 current whilst Kv1.2 was susceptible to a porphyrin bearing polyamine side chains.