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Abstract

Indiscriminate blockade of cardiac ion channels, in addition to affects on extracardiac tissues, is primarily responsible for cardiac side-effects associated with conventional antiarrhythmic drug use. The inactive R,R-enantiomers of cyclohexylbenzenacetamide analgesics (e.g., U - 50,488H and RSD920, Parke Davis compounds) exhibited antiarrhythmic activity independent of central or peripheral opioid activity. This pharmacophore offered a novel approach for rational drug design for the purpose of limiting drug toxicity. The cyclohexylbenzenacetamide structure was soon replaced with less cardiac-depressant ester derivatives. The present thesis examined a series of 16 structurally-related amino-2- cyclohexyl ester compounds to identify the chemical components within this series for cardiac ion channel blockade and, ultimately, antiarrhythmic actions against ischemiainduced arrhythmias. The compounds were tested against arrhythmias produced by myocardial ischemia and by electrical stimulation. Additional studies were performed in isolated rat ventricular cells to characterize their actions on the major depolarizing and repolarizing currents (I[sub Na] and I[sub TO], respectively). Cloned sodium channels expressed in Xenopus oocytes served as a separate cell line in which to directly evaluate effects on lNa- The major conclusions from this study were as follows: 1. In this series, anti-arrhythmic activity against ischemia-induced arrhythmias was dependent on chemical structure, in particular, with the nature of the aromatic group (R₁) and amine heterocyclic group (R₂) held in a trans position by the cyclohexyl backbone. 2. Suppression of ischemia-induced arrhythmias with minimal actions on blood pressure and heart rate was best when R₁ was 1-naphthalene and R₂ , N-morpholino (RSD1000). 3. Naphthalene analogues of RSD1000 with different ionizable nitrogen groups were shown to inhibit I[sub Na] and/or I[sub TO] currents in rat ventricular myocytes. 4. Inhibition of I[sub Na] , but not I[sub TO], was potentiated by acid pH. 5. The blocking potency for I[sub Na] was proportional to the pKa of the compound, i.e., the higher the pKa, the lower the IC₅₀. 6. Antiarrhythmic effectiveness and selectivity for ischemia-induced arrhythmias was inversely proportional to pKa. The overall finding was that suppression of ischemia-induced arrhythmias by RSD1000 was a function of mixed I[sub Na] and I[sub TO] blockade and, unlike predominantly charged antiarrhythmic agents (e.g., quinidine), the former blocking component was localized to myocardial tissue with external acid pH.