title: A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction.
abstract: 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.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Sabi
authors.forename: Declan
authors.initials: D
authors.lastname: Daly
authors.forename: Patrick
authors.initials: P
authors.lastname: Hoefer
authors.affiliation: School of Food Science and Environmental Health, College of Sciences and Health, Dublin Institute of Technology , Cathal Brugha Street, Dublin 1, Ireland.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.forename: Charles
authors.initials: C
authors.lastname: Metais
authors.affiliation: UCD School of Medicine, University College Dublin , Dublin, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: Pickering
authors.affiliation: School of Biomolecular and Biomed Science, Conway Institute , Belfield, Dublin 4, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Herron
authors.forename: Seshu Kumar
authors.initials: SK
authors.lastname: Kaza
authors.forename: Kieran
authors.initials: K
authors.lastname: Nolan
authors.forename: J Oliver
authors.initials: JO
authors.lastname: Dolly
mesh_terms: D000818:Animals; D002460:Cell Line; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D026902:Potassium Channel Blockers; D011758:Pyrroles; D051662:Kv1.1 Potassium Channel