title: Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca(2+)-activated K(+) channel blockers.
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.
authors.affiliation: Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium.
authors.forename: Amaury
authors.initials: A
authors.lastname: Graulich
authors.forename: Cédric
authors.initials: C
authors.lastname: Lamy
authors.forename: Livia
authors.initials: L
authors.lastname: Alleva
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dilly
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Vincent
authors.initials: V
authors.lastname: Seutin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C529699:AG525E1; D000588:Amines; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D044005:Tetrahydroisoquinolines