TOPIC

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

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

Year

2017

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.

Go to journal

Get in Touch

We strive to provide the best for our customers, and we are always ready to help. Please let us know if you have a question for us.

Follow us