Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker

Biomed Pharmacother. 2018 Oct:106:510-522. doi: 10.1016/j.biopha.2018.06.157. Epub 2018 Jul 11.

Abstract

Background: RSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors.

Methods: The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity.

Results: In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized.

Conclusions: RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.

Keywords: Antiarrhythmic; Electrophysiology; Langendorff; Local anesthetic; Myocyte; Neuromuscular; Pharmacokinetics; RSD921; Sodium and potassium blocker; Toxicology.

MeSH terms

  • Action Potentials
  • Administration, Intravenous
  • Anesthetics, Local / administration & dosage
  • Anesthetics, Local / pharmacokinetics
  • Anesthetics, Local / pharmacology*
  • Anesthetics, Local / toxicity
  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / pharmacology*
  • Anti-Arrhythmia Agents / toxicity
  • Antihypertensive Agents / pharmacology
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Guinea Pigs
  • Heart Rate / drug effects*
  • Humans
  • Injections, Intradermal
  • Isolated Heart Preparation
  • Male
  • Mice
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Neural Conduction / drug effects
  • Pain Threshold / drug effects
  • Papio
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / administration & dosage
  • Sodium Channel Blockers / pharmacokinetics
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channel Blockers / toxicity
  • Sodium Channels / drug effects*
  • Sodium Channels / metabolism
  • Thiophenes / pharmacology*
  • Time Factors
  • Xenopus laevis

Substances

  • Anesthetics, Local
  • Anti-Arrhythmia Agents
  • Antihypertensive Agents
  • Pyrroles
  • Sodium Channel Blockers
  • Sodium Channels
  • Thiophenes
  • PD 117302