Abstract
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.
MeSH terms
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Acrylamides / chemical synthesis*
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Acrylamides / chemistry
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Acrylamides / pharmacology
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Animals
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Cinnamates / chemical synthesis*
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Cinnamates / chemistry
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Cinnamates / pharmacology
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Cortical Spreading Depression / drug effects
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Humans
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KCNQ2 Potassium Channel
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Mice
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Oocytes / drug effects
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Oocytes / physiology
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Patch-Clamp Techniques
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Potassium Channels / drug effects*
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Potassium Channels / physiology
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Potassium Channels, Voltage-Gated
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Stereoisomerism
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Structure-Activity Relationship
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Xenopus laevis
Substances
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Acrylamides
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Cinnamates
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KCNQ2 Potassium Channel
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KCNQ2 protein, human
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Morpholines
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N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide
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N-(1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl)-3-(4-fluorophenyl)acrylamide
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Potassium Channels
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Potassium Channels, Voltage-Gated