Dataset Information

Trapping and dissociation of propafenone derivatives in HERG channels.

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.

SUBMITTER: Windisch A

PROVIDER: S-EPMC3057292 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Publications

Trapping and dissociation of propafenone derivatives in HERG channels.

Windisch A A Timin En E Schwarz T T Stork-Riedler D D Erker T T Ecker Gf G Hering S S

British journal of pharmacology 20110401 7

<h4>Background and purpose</h4>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 dissoc ...[more]

PMID: 21175572

Similar Datasets

Project description:1. The inhibition of the cardiac 'rapid' delayed rectifier current (I(Kr)) and its cloned equivalent HERG mediate QT interval prolonging effects of a wide range of clinically used drugs. In this study, we investigated the effects of the Class Ic antiarrhythmic agent flecainide (FLEC) on ionic current (I(HERG)) mediated by cloned HERG channels at 37 degrees C. We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class Ia); lignocaine (LIG, Class Ib) and propafenone (PROPAF, Class Ic). 2. Whole cell voltage clamp recordings of I(HERG) were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I(HERG) 'tails' following test pulses to +30 mV with an IC(50) of 3.91+/-0.68 microM (mean+/-s.e.mean) and a Hill co-efficient close to 1 (0.76+/-0.09). 3. In experiments in which I(HERG) tails were monitored following voltage commands to a range of test potentials, I(HERG) inhibition by FLEC was observed to be voltage-dependent and to be associated with a approximately -5 mV shift of the activation curve for the current. Voltage-dependence of inhibition was greatest over the range of potentials corresponding to the steep portion of the I(HERG) activation curve. The time-course of I(HERG) tail deactivation was not significantly altered by FLEC. 4. In experiments in which 10 s depolarizing pulses were applied from -80 to 0 mV, the level of current inhibition by FLEC did not increase between 1 and 10 s. Some time-dependence of inhibition was observed during the first 200 - 300 ms of depolarization. This observation and the voltage-dependence of inhibition are collectively consistent with FLEC exerting a rapid open channel state inhibition of I(HERG). 5. Under similar recording conditions QUIN inhibited I(HERG) with an IC(50) of 0.41+/-0.04 microM and PROPAF inhibited I(HERG) with an IC(50) of 0.44+/-0.07 microM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6. LIG showed little effect on I(HERG) at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC(50) was 262.90+/-22.40 microM. 7. Our data are consistent with FLEC, PROPAF and QUIN exerting I(HERG) blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN=PROPAF>FLEC>>LIG.

Dataset Information

Trapping and dissociation of propafenone derivatives in HERG channels.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Trapping and dissociation of propafenone derivatives in HERG channels.

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