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


Journal: Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6b01262
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Author(s): Ahmed Al-Sabi, Declan Daly, Patrick Hoefer, Gemma K. Kinsella, Charles P. E. Metais, Mark Pickering, Caroline Herron, Seshu Kumar Kaza, Kieran J. Nolan, and J Oliver Dolly


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-polarising K+currents. Modelling of interactions with the extracellular pore in a Kv1.1 deduced-structure identified a diaryldi-(2-pyrrolyl)methane (DPM) as a suitable scaffold, with optimised alkyl ammonium side chains. The resultant synthesised 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 inhibited preferentially channels containing 2 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.