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The effects of changes at the nitrogens on the pharmacological profile of a series of six analogues of rsd939 Kertesz, Ron


The selection of an appropriate therapy for ventricular arrhythmias is complicated by use of therapeutic agents which have several modes of action as well as numerous toxic effects. Attempts to improve existing agents by systematic modification of their chemical structure has had little success. Chronic use of currently available agents is not recommended, and most of these are reserved for acute use in individuals with recent infarcts. The purpose of this study was to examine a new family of ion channel blocking agents, developed by Rhythm Search Developments Ltd. (RSD), with possible application as antiarrhythmic agents. RSD's investigators discovered that a known κ-opioid agonist, U50,488H (RSD 925), had sodium channel blocking actions. RSD then developed a series of compounds which show some limited 3- dimensional similarity to RSD925. Seven of these compounds (RSD 939, RSD 952, RSD 961, RSD 969, RSD 971, RSD 981, and RSD 988) were examined in an attempt to correlate changes at the two structural hetero atoms (labeled as X1 or X2) with changes in sodium and potassium channel blocking activity, toxicity, and electrophysiological effects on isolated whole cells. For this study RSD939 was used as the prototype compound to which the other compounds were compared. The pharmacological profile of the compounds was determined by in vivo experiments on rats and mice. Drug effects were determined by recording blood pressure (BP), heart rate, (HR), and electrocardiogram (ECG) in pentobarbitone-anaesthetized rats given bolus administrations of drug. The same measurements were made in anaesthetized rats receiving infusions of drug. In addition, the infused animals were also subjected to electrical stimulation of the heart in order to measure several of its electrical parameters. The electrical parameters measured were: the threshold current for capture (iT), the threshold pulse duration for capture (tT), the threshold current for induction of ventricular fibrillation (VFT), the effective refractory period (ERP), and the maximum following frequency (MFF). Lethality of the compounds was tested using both rats and mice. Finally, effects of the compounds on single ion channels were assessed in vitro using patch clamp techniques. Changes to the amide nitrogen at the XI position had effects on the pharmacological profile of the compounds. Changing the tertiary amide (RSD 939) to a secondary amide (RSD988) seemed to decrease both sodium channel and potassium channel blocking activity. The secondary amide was also less toxic, but appeared to be a more potent affector of blood pressure (BP) and heart rate (HR) changes. Substitution of an ester linkage (RSD 952) for the amide linkage of RSD 939 reduced potency for ion channel blockade even more than the change to a secondary amide. This ester was less toxic than either RSD 939 or RSD 988. RSD 952 also had less effect on HR and BP than either RSD 939 or RSD 988. Changes to the substitution pattern on the nitrogen at X2 also had distinct effects. Converting the tertiary pyrrollidino amine nitrogen (RSD939) to a quaternary methyl pyrrollidinium nitrogen (RSD971) decreased ion channel blocking activity while leaving toxicity (lethality and morbidity) either unchanged or slightly increased. It appeared that the most important determinants of activity for the compounds examined in this study were the water solubility of the compounds and the pKa of the nitrogen at the X2 position. It is evident that changes to the regions around the nitrogens at positions X1 and X2 affected the activity of these antiarrhythmic agents. It is also evident that a separation of the pharmacophores for Na and K channels, as well as those for morbidity and lethality effects, is possible. Further examination of a larger number of compounds will lead to a better understanding of the chemical structure requirements for effective antiarrhythmic design.

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