title: Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels.
abstract: OBJECTIVE
  This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels.
  
  
  METHODS
  Human ether-à-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (I(K)) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer.
  
  
  RESULTS
  Both DC031050 and dofetilide potently inhibited hERG currents with IC(50) values of 2.3 ± 1.0 and 17.9 ± 1.2 nmol/L, respectively. DC031050 inhibited the I(K) current with an IC(50) value of 2.7 ± 1.5 μmol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 μmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of I(K), or the rate of I(K) from inactivation. Intracellular application of DC031050 (5 μmol/L) was insufficient to inhibit I(K). DC031050 up to 10 μmol/L had no effects on KCNQ2 and Kv1.2 channel currents.
  
  
  CONCLUSIONS
  DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Hai-feng
authors.initials: HF
authors.lastname: Sun
authors.forename: Ping-zheng
authors.initials: PZ
authors.lastname: Zhou
authors.forename: Chao-ying
authors.initials: CY
authors.lastname: Ma
authors.forename: Guo-yuan
authors.initials: GY
authors.lastname: Hu
authors.forename: Hua-liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Zhao-bing
authors.initials: ZB
authors.lastname: Gao
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; C575345:DC031050; D051638:Ether-A-Go-Go Potassium Channels; D051656:KCNQ Potassium Channels; D051663:Kv1.2 Potassium Channel; D010627:Phenethylamines; D013449:Sulfonamides; D011188:Potassium