Structure-activity relationships of antiarrhythmic 6-substituted decahydroisoquinolines.
A series of diastereoisomeric 6-benzoyloxy- and 6-benzamido-2-methyldecahydroisoquinolines has been prepared and screened for antiarrhythmic effectiveness. In a continuation of our interest in identifying significant physicochemical properties of antiarrhythmic decahydroisoquinolines, octanol-water partition coefficients and pKa values have been determined for each member of the series. In general, antiarrhythmic activities superior to that of quinidine were observed. From a general structure-activity viewpoint, substitutions possessing greater lipophilicities produced compounds with superior antiarrhythmic properties. However, there appears to be optimal lipophilic character beyond which increased lipophilicity results in a decrease in antiarrhythmic potency. No discernible correlations with pKa values were evident. As noted in our earlier studies the esters were more potent and more lipophilic than the corresponding amides. No obvious correlations with stereochemistry were found; however, in three pairs of diastereoisomers, the more lipophilic cis compounds were found to be the superior isomers. A surprisingly high potency was noted with a tetrahydroisoquinoline benzamide--a finding unexpected from our earlier work. The 3,4-dichlorobenzamido grouping appeared to be the substituting moiety for optimal antiarrhythmic effectiveness.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002725:Chloroform; D005260:Female; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D007700:Kinetics; D007928:Lethal Dose 50; D051379:Mice; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D002725:Chloroform