Synthesis and antiarrhythmic properties of some 5-benzamido-2-methyl-trans-decahydroisoquinolines.
An efficient synthetic route to produce exclusively 5-amino-2-methyl-trans-decahydroisoquinoline is described. The preparation of ten 5-benzamido-2-methyl-trans-decahydroisoquinolines from this precursor has been accomplished, and each has been screened for both antiarrhythmic potency and toxicity. The selection of structures for synthesis was based on our previous report of the significant antiarrhythmic potency of 5-(3,4,5-trimethoxybenzamido)-2-methyl-trans-decahydroisoquinoline (15). Molecular modifications of this single structure were made in order to ascertain structure-activity relationships in this group of compounds. All the compounds synthesized showed significant antiarrhythmic potency. The lipophilicity of the benzamide moiety appears to play a significant role in developing optimal antiarrhythmic potency. Interestingly and surprisingly, the most potent compound of the present study was 15, a compound described in our original work. Structure-activity relationships of the series are described.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D005260:Female; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D012995:Solubility; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines