Synthesis and structure-activity relationship of acrylamides as KCNQ2 potassium channel openers.
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
Wu
Yong-Jin
YJ
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. yong-jin.wu@bms.com
He
Huan
H
Sun
Li-Qiang
LQ
L'Heureux
Alexandre
A
Chen
Jie
J
Dextraze
Pierre
P
Starrett
John E
JE
Boissard
Christopher G
CG
Gribkoff
Valentin K
VK
Natale
Joanne
J
Dworetzky
Steven I
SI
D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000187:drug effects; D006801:Humans; D051658:KCNQ2 Potassium Channel; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000178:Acrylamides; D002934:Cinnamates; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D009025:Morpholines; C476437:N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide; C477185:N-(1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl)-3-(4-fluorophenyl)acrylamide; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated