title: Trapping and dissociation of propafenone derivatives in HERG channels.
abstract: OBJECTIVE
  Human ether-a-go-go related gene (HERG) channel inhibitors may be subdivided into compounds that are trapped in the closed channel conformation and others that dissociate at rest. The structural peculiarities promoting resting state dissociation from HERG channels are currently unknown. A small molecule-like propafenone is efficiently trapped in the closed HERG channel conformation. The aim of this study was to identify structural moieties that would promote dissociation of propafenone derivatives.
  
  
  METHODS
  Human ether-a-go-go related gene channels were heterologously expressed in Xenopus oocytes and potassium currents were recorded using the two-microelectrode voltage clamp technique. Recovery from block by 10 propafenone derivatives with variable side chains, but a conserved putative pharmacophore, was analysed.
  
  
  RESULTS
  We have identified structural determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with 'short' side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H-bond acceptor in this region was trapped. Correlations were observed between molecular weight and onset of channel block as well as between pK(a) and recovery at rest.
  
  
  CONCLUSIONS
  The data show that extending the size of a trapped HERG blocker-like propafenone by adding a bulky side chain may impede channel closure and thereby facilitate drug dissociation at rest. The presence of an H-bond acceptor in the bulky side chain is, however, essential.
authors.affiliation: Department of Pharmacology and Toxicology University of Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Windisch
authors.forename: En
authors.initials: E
authors.lastname: Timin
authors.forename: T
authors.initials: T
authors.lastname: Schwarz
authors.forename: D
authors.initials: D
authors.lastname: Stork-Riedler
authors.forename: T
authors.initials: T
authors.lastname: Erker
authors.forename: Gf
authors.initials: G
authors.lastname: Ecker
authors.forename: S
authors.initials: S
authors.lastname: Hering
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008970:Molecular Weight; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D011405:Propafenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D011487:Protein Conformation / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011405:Propafenone; D011188:Potassium