Open Access. Powered by Scholars. Published by Universities.®
Articles 1 - 1 of 1
Full-Text Articles in Medicine and Health Sciences
A Rational Design Of A Selective Inhibitor For Kv1.1 Channels Prevalent In Demyelinated Nerves That Improves Their Impaired Axonal Conduction, Ahmed Al-Sabi, Declan Daly, Patrick Hoefer, Gemma K. Kinsella, Charles Metais, Mark Pickering, Caroline Herron, Seshu Kumar Kaza, Kieran Nolan, J. Oliver Dolly
A Rational Design Of A Selective Inhibitor For Kv1.1 Channels Prevalent In Demyelinated Nerves That Improves Their Impaired Axonal Conduction, Ahmed Al-Sabi, Declan Daly, Patrick Hoefer, Gemma K. Kinsella, Charles Metais, Mark Pickering, Caroline Herron, Seshu Kumar Kaza, Kieran Nolan, J. Oliver Dolly
Articles
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 …