Trapping and dissociation of propafenone derivatives in HERG channels

Author(s)

Alfred Windisch, Evgeny Timin, Thomas Schwarz, Daniela Stork, Thomas Erker, Gerhard Ecker, Steffen Hering

Abstract

BACKGROUND AND PURPOSE

 

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.

 

EXPERIMENTAL APPROACH

 

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.

 

KEY 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.

 

CONCLUSION AND IMPLICATIONS

 

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.

Organisation(s)

Journal

British Journal of Pharmacology

Volume

162

Pages

1542-1552

No. of pages

11

ISSN

0007-1188

DOI

https://doi.org/10.1111/j.1476-5381.2010.01159.x

Publication date

2011

Peer reviewed

Yes

Austrian Fields of Science 2012

301206 Pharmacology

Portal url

https://ucrisportal.univie.ac.at/en/publications/3624a032-7983-4751-863b-7b18e6b0c436