%0 Journal Article %J Journal of medicinal chemistry %D 2011 %T Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus %A Duque,M. D. %A Ma,C. %A Torres,E. %A Wang,J. %A Naesens,L. %A Juarez-Jimenez,J. %A Camps,P. %A F. J. Luque %A DeGrado,W. F. %A Lamb,R. A. %A Pinto,L. H. %A Vazquez,S. %K Amantadine/chemistry/pharmacology; Animals; Antiviral Agents/chemistry/pharmacology; Cell Line; Dogs; Influenza A virus/drug effects/growth & development; Magnetic Resonance Spectroscopy; Models %K Infrared; Structure-Activity Relationship; Viral Matrix Proteins/antagonists & inhibitors/chemistry; Xenopus %K Molecular; Patch-Clamp Techniques; Plaque Assay; Spectrophotometry %N 8 %P 2646 - 2657 %V 54 %X Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein. %8 2011/04/28/