Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus

J Med Chem. 2014 Jul 10;57(13):5738-47. doi: 10.1021/jm5005804. Epub 2014 Jun 30.


Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amantadine / analogs & derivatives*
  • Amines / chemical synthesis*
  • Amines / pharmacology
  • Animals
  • Dogs
  • Drug Resistance, Viral
  • Influenza A virus / drug effects*
  • Ion Channels / drug effects
  • Madin Darby Canine Kidney Cells
  • Models, Molecular
  • Mutation
  • Orthomyxoviridae Infections / drug therapy
  • Patch-Clamp Techniques
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacology
  • Structure-Activity Relationship
  • Viral Matrix Proteins / antagonists & inhibitors*
  • Viral Matrix Proteins / genetics
  • Xenopus


  • Amines
  • Ion Channels
  • M2 protein, Influenza A virus
  • Pyrrolidines
  • Viral Matrix Proteins
  • Amantadine