title: Characterization of A-935142, a hERG enhancer, in the presence and absence of standard hERG blockers.
abstract: OBJECTIVE
  In a previous study we found that A-935142 enhanced hERG current in a concentration-dependent manner by facilitating activation, reducing inactivation, and slowing deactivation (Su et al., 2009). A-935142 also shortened action potential duration (APD90) in canine Purkinje fibers and guinea pig atrial tissue. This study focused on the combined effects of the prototypical hERG enhancer, A-935142 and two hERG current blockers (sotalol and terfenadine).
  
  
  METHODS
  The whole-cell voltage clamp method with HEK 293 cells heterologously expressing the hERG channel (Kv 11.1) was used.
  
  
  RESULTS
  A-935142 did not compete with 3H-dofetilide binding, suggesting that A-935142 does not overlap the binding site of typical hERG blockers. In whole-cell voltage clamp studies we found: 1) 60 μM A-935142 enhanced hERG current in the presence of 150 μM sotalol (57.5±5.8%) to a similar extent as seen with A-935142 alone (55.6±5.1%); 2) 150 μM sotalol blocked hERG current in the presence of 60 μM A-935142 (43.5±1.5%) to a similar extent as that seen with sotalol alone (42.0±3.2%) and 3) during co-application, hERG current enhancement was followed by current blockade. Similar results were obtained with 60 nM terfenadine combined with A-935142.
  
  
  CONCLUSIONS
  These results suggest that the hERG enhancer, A-935142 does not compete with these two known hERG blockers at their binding site within the hERG channel. This selective hERG current enhancement may be useful as a treatment for inherited or acquired LQTS (Casis et al., 2006).
authors.affiliation: Department of Integrative Pharmacology, Abbott, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA. xiaoqin.liu@abbott.com
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.forename: James T
authors.initials: JT
authors.lastname: Limberis
authors.forename: Zhi
authors.initials: Z
authors.lastname: Su
authors.forename: Kathryn
authors.initials: K
authors.lastname: Houseman
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Diaz
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000704:Analysis of Variance; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism*; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism; D016593:Terfenadine / Q000494:pharmacology; D014316:Tritium
chemical_list: C540927:(4-(4-(5-trifluoromethyl-1H-pyrazol-3-yl)phenyl)cyclohexyl)acetic acid; D000085:Acetates; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010627:Phenethylamines; D011720:Pyrazoles; D013449:Sulfonamides; D014316:Tritium; D016593:Terfenadine; D013015:Sotalol; C063533:dofetilide