title: Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel.
abstract: OBJECTIVE
  We aimed to characterize the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded K(+) channel (Kv 11.1).
  
  
  METHODS
  Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology.
  
  
  RESULTS
  AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 μM respectively. At 100 μM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at -30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv 4.3-hKChIP2.2, hCav 3.2 and hKv 1.5 and activated hCav 1.2/β2/α2δ channels.
  
  
  CONCLUSIONS
  The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome.
authors: Institute of Neurology, Faculty of Brain Sciences, University College London, London, Middlesex, UK.
authors: R
authors: R
authors: Mannikko
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: M H
authors: MH
authors: Bridgland-Taylor
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: H
authors: H
authors: Pye
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: S
authors: S
authors: Swallow
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: N
authors: N
authors: Abi-Gerges
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: M J
authors: MJ
authors: Morton
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: C E
authors: CE
authors: Pollard
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000605333:N-(3-(1H-benzimidazol-2-yl)-4-chlorophenyl)pyridine-3-carboxamide; D009536:Niacinamide