title: Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent.
abstract: OBJECTIVE
  To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.
  
  
  METHODS
  The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.
  
  
  RESULTS
  In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED₅₀ value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and V(max), prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V(max) in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I(Na) (IC₅₀=26.9 μmol/L) and I(Ca,L)(IC₅₀=69.2 μmol/L), whereas the inward rectifier (I(K1)) and the delayed rectifier potassium currents (I(K)) were unaffected.
  
  
  CONCLUSIONS
  As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China. dlbai@mail.shcnc.ac.cn
authors.forename: Dong-Lu
authors.initials: DL
authors.lastname: Bai
authors.forename: Wei-Zhou
authors.initials: WZ
authors.lastname: Chen
authors.forename: Yun-Xin
authors.initials: YX
authors.lastname: Bo
authors.forename: Yue-Li
authors.initials: YL
authors.lastname: Dong
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Kang
authors.forename: Wei-Kang
authors.initials: WK
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Hu
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
mesh_terms: D000157:Aconitine / Q000633:toxicity; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010042:Ouabain / Q000633:toxicity; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D015222:Sodium Channels; D013463:Sulfuric Acid Esters; C558473:sulcardine sulfate; D010042:Ouabain; D000157:Aconitine