Referenced in: none

Automatically associated channels: Kir2.3 , SK1 , SK2 , SK3

Title: Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca(2+)-activated K(+) channel blockers.

Authors: Amaury Graulich, Cédric Lamy, Livia Alleva, Sébastien Dilly, Philippe Chavatte, Johan Wouters, Vincent Seutin, Jean-François Liégeois

Journal, date & volume: Bioorg. Med. Chem. Lett., 2008 Jun 1 , 18, 3440-5

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18436444

Abstract
So far, small conductance Ca(2+)-activated K(+) channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K(i)=293nM) approximately 100-fold higher than the tertiary compound laudanosine (K(i) approximately 30muM) and similar to the charged compound dequalinium (K(i)=221nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets.