New antiarrhythmic agents. 4. 1'-(Aminoalkyl)-1,2,3,4-tetrahydronaphthalene-1-spiro-3'-pyrrolidine-2',5'-dione derivatives.
A series of 33 1'-(Aminoalkyl)-1,2,3,4-tetrahydronaphthalene-1-spiro-3'-pyrrolidine-2',5'-dione derivatives was tested for antiarrhythmic and toxic effects in mice and dogs. In mice, 31 compounds produced some protection against chloroform-induced tachyarrhythmias at subcutaneous doses of 100 mg/kg, and 6 compounds produced no detectable toxicity at doses protecting 80% or more of the animals. Seven of the more potent and nontoxic derivatives were tested in dogs with surgically induced myocardial infarctions. All produced distinct antiarrhythmic effects at doses considerably lower than doses of lidocaine or tocainide producing comparable effects. The principal toxic effects observed in dogs were convulsion and depression of intracardiac conduction; they occurred generally at higher doses than those leading to antiarrhythmic effect. Several compounds also suppressed digitalis-induced arrhythmias in anesthetized dogs. Half-lives and total body clearance in dogs were determined for three compounds; two had half-lives comparable to that of tocainide, a long-acting, orally active antiarrhythmic agent, in clinical trials.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D007700:Kinetics; D009281:Naphthalenes / Q000138:chemical synthesis*; D011760:Pyrrolidinones / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis*
D000889:Anti-Arrhythmia Agents; D009281:Naphthalenes; D011760:Pyrrolidinones; D013764:Tetrahydronaphthalenes