Potassium channels that are encoded by the human Ether-à-go-go Related Gene (hERG) conduct the rapid delayed rectifier (IKr) current which is important in controlling the duration of both the ventricular action potential and the QT interval of the electrocardiogram (Sanguinetti & Tristani-Firouzi 2006; Hancox et al. 1998). Pharmacological inhibition of hERG by structurally and therapeutically diverse drugs is associated with acquired long QT syndrome and Torsades de Pointes (TdP) arrhythmia (Sanguinetti & Tristani-Firouzi 2006; Hancox et al. 2008). Understanding the structural basis of drug-hERG interactions is therefore imperative for safer drug design. Recently, substituted diphenylpropanamines have been designed as “minimally structured” high affinity hERG channel inhibitors (Cavalli et al. 2012). This study was undertaken to characterise the underlying nature of the interactions with hERG of one of these inhibitors: “Cavalli-2” (Cavalli et al. 2012). Experiments were performed on HEK-293 cells stably expressing wild-type hERG channels. Whole-cell patch clamp measurements of IhERG were made at 37°C. Data are presented as mean ± SEM, with at least 5 replicates per observation. Potency of IhERG block by Cavalli-2 was assessed by measuring tail currents at -40 mV following 2s depolarisations to +20 mV; this yielded a half-maximal inhibitory concentration (IC50) of 35.6 ± 0.06 nM (Hill coefficient 0.69 ± 0.08). Through the application of voltage commands to a range of test potentials, IhERG inhibition by Cavalli-2 was found to be voltage-dependent, with an increase in block coinciding with the steep portion of the IhERG activation curve; this is consistent with gating dependent block. During an ‘envelope of tails’ protocol, comparatively little IhERG block was observed for short depolarisations, with inhibition increasing with duration of the applied depolarising command. Half-maximal inactivation of IhERG exhibited a modest left-ward shift (of 6.4 ± 0.5 mV) in the presence of Cavalli-2. Depolarisation to +40 mV in order to promote inactivation, during a sustained command to 0 mV, produced a statistically significant (two-tailed paired t test, P < 0.05) decrease in IhERG inhibition. Collectively, the results of this study show that Cavalli-2 exhibits potent IhERG inhibition that is contingent upon channel gating, involving drug interactions with both activated and inactivated channel states. This minimally structured hERG channel blocker thus exhibits actions similar to canonical high potency hERG blockers, despite being incapable of forming hydrogen bonds with amino-acid residues lining the drug binding pocket.