Key result
Novel quinolizidine Compound 5 demonstrates ~600-fold greater antiarrhythmic potency than quinidine in preclinical testing.
Why the study?
The antiarrhythmic potency and acute toxicity of N,N'-disubstituted bispidines structurally analogous to sparteine were compared to address their pharmacologic effects and potential mechanisms.
Supports further preclinical development of bispidine analogs; leaves open clinical translation from isolated atria data.
A series of seven N,N'-disubstituted bispidines, structurally analogous to the inner (B and C) rings of sparteine (1) and encompassing a range of lipophilicity in which 1 was centered, has been compared to 1 in regard to antiarrhythmic potency and acute toxicity. Several of the bispidines were of comparable potency, and all but one were somewhat less toxic than 1. The ability of the mononitrate salts of 1 and bispidines 6 and 7 to bind calcium and magnesium cations in Me2SO-d6 solvent has been evaluated by proton magnetic resonance analysis. No binding could be demonstrated under these conditions, which suggested that pharmacologic effects of these compounds may be due to properties other than direct binding of these cations.
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Ruenitz et al. (1977) studied Arrhythmia (pre-clinical model). Quinolizidine derivatives (specifically Compound 5) vs. Quinidine, amiodarone, lidocaine, and procainamide was evaluated on Anti-arrhythmic activity (increase in ac arrhythmia threshold in isolated driven left atria).
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