title: Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine.
abstract: OBJECTIVE
  Chloroquine, an anti-malarial quinoline, is structurally similar to quinidine. Both drugs have been shown to block ion channels. We tested the hypothesis that chloroquine's mode of interaction with the vestibule of the cytoplasmic domain of the inward rectifier potassium channel Kir2.1 makes it a more effective I(K1) blocker and anti-fibrillatory agent than quinidine.
  
  
  RESULTS
  We used comparative molecular modelling and ligand docking of the three-dimensional structures of quinidine and chloroquine in the intracellular domain of Kir2.1. Simulations predicted that chloroquine effectively blocks potassium flow by binding at the centre of the ion permeation vestibule of Kir2.1. In contrast, quinidine binds the vestibular side, only partially blocking ion movement. We tested the modelling predictions in Kir2.1-expressing human embryonic kidney (HEK)-293 cells. The half-maximal inhibitory concentration for chloroquine block of I(K1) was 1.2 µM, while that of quinidine was 57 µM. Finally, we used optical mapping of Langendorff-perfused mouse hearts with cardiac-specific Kir2.1 up-regulation to compare the anti-fibrillatory effects of the drugs. In five of six hearts, 10 μM quinidine slowed the frequency but did not terminate the tachyarrhythmia. In five of five hearts, 10 μM chloroquine terminated the arrhythmia, restoring sinus rhythm.
  
  
  CONCLUSIONS
  Quinidine only partially blocks I(K1). Chloroquine binds at the centre of the ion permeation vestibule of Kir2.1, which makes it a more effective I(K1) blocker and anti-fibrillatory agent than quinidine. Integrating the structural biology of drug-ion channel interactions with cellular electrophysiology and optical mapping is an excellent approach to understand the molecular mechanisms of anti-arrhythmic drug action and for drug discovery.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, 5025 Venture Dr., Ann Arbor, MI 48108, USA.
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer-Villada
authors.forename: Angelica
authors.initials: A
authors.lastname: López-Izquierdo
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Chapula
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002738:Chloroquine / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011802:Quinidine / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D002738:Chloroquine; D011802:Quinidine