Synthesis and biological action of the aminotetrahydroisoquinocarbazoles and related compounds: a new class of compounds with antiarrhythmic activity.
A series of 12-aminotetrahydroisoquinocarbazoles and related compounds were synthesized using an intramolecular Diels-Alder reaction and screened for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice. Several compounds showed more potent activity than disopyramide. There was some correlation between substituents on aromatic ring and angular position, and antiarrhythmic activity. An amino group or some functional groups containing an amino group on C-12 seemed to be essential to exhibit the activity. Ring size also influenced the activity. The compound (+)-10 (RS-2135) had the most favorable combination of antiarrhythmic activity and toxicity and was selected for further evaluation.
Shimoji
Y
Y
Sankyo Research Laboratories, Sankyo Company, Ltd., Tokyo, Japan.
Tomita
K
K
Hashimoto
T
T
Saito
F
F
Morisawa
Y
Y
Mizuno
H
H
Yorikane
R
R
Koike
H
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002725:Chloroform; D004285:Dogs; D005260:Female; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D002227:Carbazoles; D007546:Isoquinolines; C073517:RS 2135; D002725:Chloroform