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10 Voltage-dependent affinity of some compounds that inhibit hERG: rapid dissociation and reassociation?
  1. J T Milnes1,2,
  2. M McPate1,3,
  3. C E Dempsey1,
  4. R S Duncan1,
  5. J L Leaney4,
  6. D J Leishman4,5,
  7. J C Hancox1,
  8. H J Witchel1,6
  1. 1University of Bristol, Bristol, UK
  2. 2Xention, Cambridge, UK
  3. 3Novartis, Horsham, UK
  4. 4Pfizer Global Research, Sandwich, UK
  5. 5Eli Lilly, Indiana, USA
  6. 6Brighton and Sussex Medical School, Brighton, East Sussex, UK


Rationale Voltage-dependent changes in hERG inhibitor-induced functional inhibition of the hERG potassium (K+) channel can potentially be ascribed not only to state-dependent changes in affinity of the inhibitor for its binding site but also to allosteric modulation of hERG's gating kinetics and to two-step inhibition processes incorporating an initial non-inhibiting inhibitor–channel encounter complex.1 In kinetics modulation models and in encounter complex models the inhibitor–channel interaction involves constant residency, while voltage-dependent changes in affinity will manifest rapid equilibrium of the inhibitor–channel complex in some protocols.2

Methods Patch clamp of hERG-transfected cells in the ‘voltage clamp’ mode was performed with a range of protocols involving washing a range of hERG inhibitors on or off during the protocol.

Results The behaviours of both selected inhibitors with positive voltage- and frequency-dependence and of an inverse voltage-dependent inhibitor (BeKm-1) are indicative of apparent changes in channel inhibition concordant with rapid equilibrium.

Conclusion This rapid equilibrium, if fast enough, will affect the predicted net effect on a cardiac hERG channel undergoing voltage cycling.

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