The present project is based on a collaborative effort by medicinal and physical chemists, electrophysiologists and nuclear pharmacists for the purpose of studying the properties of a newly synthetized class of anti-arrhythmic agents, 3,7-diheterabicyclo[3.3.1]nonanes. Our purpose is to study the electrophysiology, hemodynamic effects, chemistry and myocardial distribution of this new class of agents. Electrophysiology - The purposes of the electrophysiology section is mainly to test the hypothesis that the 3,7-diheterabicyclo[3.3.1]nonanes and such clinically useful antiarrhythmic agents as lidocaine and amiodarone have a common mechanism of action on a basic level. Specifically, we postulate that their main action is to directly and selectively depress conduction of abnormal myocardium which can participate in reentry circuits. Induced ventricular tachycardia in 2 animal preparations of acute and subacute myocardial infarction will be used to simulate two forms fo malignant, sustained ventricular tachycardia seen in clinical situations which are associated with sudden death. In vitro studies, using standard microelectrode techniques, will determine the cellular electrophysiologic effects of these anti-arrhythmic agents on normal and abnormal tissues. Chemistry - The objective of the chemical research is to develop new strategies for the introduction of heteroatoms into bicyclic systems. Structural modifications such as variations of ring size, addition of functional groups to the bicyclic system will be tested to significantly influence the drugs' potency and toxicity. Complete structure elucidation will be performed via the use of infra-red, nuclear magnetic resonance, X-ray diffraction and mass-spectral analyses. In addition to the 3,7-diheterabicyclo[3.3.1]nonanes and derivatives, the work will also be devoted to the development of synthetic approaches to larger rings in the bicyclic framework. Myocardial Drug Distribution - Using a new methodology, developed in our laboratories, of imaging """"""""bread-loaf"""""""" sections of the entire dog heart, we intend to measure the distribution of the 3,7-diheterabicyclo[3.3.1]nonanes in the infarcted hearts. The new agents will have a radioactive selenium tag incorporated into the molecule in order for us to use an Anger camera to image the sections from the entire infarcted heart and determine tissue levels of anti-arrhythmic agent. Technetium-99m labeled microspheres will be used for simulatenous blood flow mapping images also obtained via the Anger camera methodology.
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| Patterson, E; Scherlag, B J; Berlin, K D et al. (1991) Electrophysiological actions of BRB-I-28 in canine myocardial tissues. J Pharmacol Exp Ther 259:558-65 |
| Scherlag, B J; Patterson, E; Lazzara, R (1990) Seasonal variation in sudden cardiac death after experimental myocardial infarction. J Electrocardiol 23:223-30 |
| Thompson, M D; Smith, G S; Berlin, K D et al. (1987) Synthesis and antiarrhythmic properties of novel 3-selena-7-azabicyclo[3.3.1]nonanes and derivatives. Single-crystal X-ray diffraction analysis of 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one and 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchl J Med Chem 30:780-8 |
