Synthesis and structure-activity relationship of acrylamides as KCNQ2 potassium channel openers.

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.

• Authors: Yong-Jin Wu, Huan He, Li-Qiang Sun, Alexandre L'Heureux, Jie Chen, Pierre Dextraze, John E Starrett Jr, Christopher G Boissard, Valentin K Gribkoff, Joanne Natale, Steven I Dworetzky
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 11 Pg. 2887-96 (May 20 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15139767 (Publication Type: Journal Article)

Chemical References

• Acrylamides
• Cinnamates
• KCNQ2 Potassium Channel
• KCNQ2 protein, human
• Morpholines
• N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide
• N-(1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl)-3-(4-fluorophenyl)acrylamide
• Potassium Channels
• Potassium Channels, Voltage-Gated

Topics

• Acrylamides (chemical synthesis, chemistry, pharmacology)
• Animals
• Cinnamates (chemical synthesis, chemistry, pharmacology)
• Cortical Spreading Depression (drug effects)
• Humans
• KCNQ2 Potassium Channel
• Mice
• Morpholines (chemical synthesis, chemistry, pharmacology)
• Oocytes (drug effects, physiology)
• Patch-Clamp Techniques
• Potassium Channels (drug effects, physiology)
• Potassium Channels, Voltage-Gated
• Stereoisomerism
• Structure-Activity Relationship
• Xenopus laevis