(S)-N-[1-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons.
(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.
Wu
Yong-Jin
YJ
Department of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. yong-jin.wu@bms.com
Boissard
Christopher G
CG
Chen
Jie
J
Fitzpatrick
William
W
Gao
Qi
Q
Gribkoff
Valentin K
VK
Harden
David G
DG
He
Huan
H
Knox
Ronald J
RJ
Natale
Joanne
J
Pieschl
Rick L
RL
Starrett
John E
JE
Sun
Li-Qiang
LQ
Thompson
Mark
M
Weaver
David
D
Wu
Dedong
D
Dworetzky
Steven I
SI
D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051658:KCNQ2 Potassium Channel; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D013329:Structure-Activity Relationship
D000178:Acrylamides; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C496915:Kcnq2 protein, rat; C492891:N-(1-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo(1,4)oxazin-6-yl)ethyl)-3-(2-fluorophenyl)acrylamide; D010078:Oxazines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated