SYNTHESIS, PHARMACOLOGICAL CHARACTERIZATION, AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSES OF 3,7,9,9-TETRAALKYLBISPIDINES - DERIVATIVES WITH SPECIFIC BRADYCARDIAC ACTIVITY

A series of 3,7,9,9-tetraalkyl-3,7-diazabicyclo[3.3.1]nonane derivativ es (bispidines) was synthesized and identified as potential antiischem ic agents. Pharmacological experiments in vitro as well as in vivo are described, and the results are listed. For selection of those compoun ds fitting best to the desired profile of a specific bradycardic antia nginal agent-decrease in heart rate without affecting contractility an d blood pressure-these results were scored and ranked. Quantitative st ructure-activity relationship (QSAR) analyses were performed and discu ssed a posteriori by means of Hansch, nonelementary discriminant and f actor analysis to get insight into the molecular features determining the biological profile. Highly significant equations were obtained, in dicating hydrophobic and steric effects. Both pharmacological ranking and QSAR considerations showed compound 6 as the optimum within the st ructural class under investigation. Compound 6 (tedisamil, KC8857) has been selected as the most promising compound and was chosen for furth er pharmacological and clinical investigations as an antiischemic drug .