title: CPU86017: a novel Class III antiarrhythmic agent with multiple actions at ion channels.
abstract: CPU86017 is a novel Class III antiarrhythmic agent derived from berberine and with an improved pharmacological profile, solubility and bioavailability. It is active in suppressing arrhythmias in several animal models. The ED(50) of CPU86017 for suppressing ischemia/reperfusion arrhythmias in rats was 0.22 mg/kg against 2.23 mg/kg for lidocaine. CPU86017 is about 10-fold more potent than lidocaine. It blocks I(K(R.tail)), I(K(S)), and I(Ca(L)) currents with IC(50) values of 25, 14.4, and 11.5 microM, respectively. The plasma t(1/2) of CPU86017, i.v. bolus, in rabbits and dogs is approximately 90 min. The effective plasma levels of CPU86017 in rabbits required to delay the appearance of oubain-induced ventricular arrhythmias is in the range of 0.13-0.31 microg/mL. Higher levels of the drug are required to eliminate ventricular arrhythmias produced by two-stage ligation of the coronary artery in anesthetized dogs. Drug levels in myocardium are much higher than in plasma. CPU80617 has an antioxidant effect that is likely to contribute to its antiarrhythmic activity. The abnormal expression of the ryanodine receptor type 2 (RyR2) and of FKBP12.6 is reduced by CPU80617 during its ventricular tachyarrhythmia-suppressing action. CPU86017 appears to be a promising antiarrhythmic agent with a cardioprotective action. It can be expected to protect from malignant arrhythmias and sudden cardiac death by suppressing molecular events caused by channelopathies.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China. dezaidai@vip.sina.com
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000503:physiopathology / Q000517:prevention & control; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D015394:Molecular Structure; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control
chemical_list: C400084:4-chlorobenzyltetrahydroberberine; D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D001599:Berberine