The molecular features of verapamil that promote myocardial enzyme leakage.
The effects of verapamil (Vp) and four Vp derivatives on myocardial enzyme leakage were compared. Norverapamil (N-demethylated; D591) and acyano-Vp (the nitrile-substituted H-derivative; Sz65) produced leakage comparable to and greater than that of verapamil, respectively. In contrast, the derivative with hydroxyl substitution of all four methoxy groups (D573) and the quaternary amine salt derivative (D575) were inert. These data indicate that both lipid solubility and an ionizable amine were critical to the membrane disruptive effect of verpamil.
Cohen
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L
Morgan
J
J
Kezdy
F
F
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007477:Ions; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013997:Time Factors; D014700:Verapamil / Q000031:analogs & derivatives / Q000494:pharmacology*
D007477:Ions; D014700:Verapamil; D003402:Creatine Kinase; D002118:Calcium