TY - JOUR
T1 - Bis-tetrahydroisoquinoline derivatives
T2 - AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers
AU - Graulich, Amaury
AU - Lamy, Cédric
AU - Alleva, Livia
AU - Dilly, Sébastien
AU - Chavatte, Philippe
AU - Wouters, Johan
AU - Seutin, Vincent
AU - Liégeois, Jean François
PY - 2008/6/1
Y1 - 2008/6/1
N2 - So far, small conductance Ca2+-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 (Ki = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (Ki ∼ 30 μM) and similar to the charged compound dequalinium (Ki = 221 nM). 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.
AB - So far, small conductance Ca2+-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 (Ki = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (Ki ∼ 30 μM) and similar to the charged compound dequalinium (Ki = 221 nM). 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.
KW - Apamin
KW - Motor activity
KW - Neurons
KW - Patch-clamp
KW - Stereoisomer
KW - Tetrahydroisoquinoline
UR - http://www.scopus.com/inward/record.url?scp=44149085660&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2008.03.069
DO - 10.1016/j.bmcl.2008.03.069
M3 - Article
C2 - 18436444
AN - SCOPUS:44149085660
SN - 0960-894X
VL - 18
SP - 3440
EP - 3445
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
IS - 11
ER -