Tenthorey P A, Ronfeld R A, Feldman H S, Sandberg R V, McMaster P D, Smith E R
J Med Chem. 1981 Jan;24(1):47-53. doi: 10.1021/jm00133a011.
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.
对一系列33种1'-（氨基烷基）-1,2,3,4-四氢萘-1-螺-3'-吡咯烷-2',5'-二酮衍生物进行了小鼠和犬的抗心律失常及毒性作用测试。在小鼠中，31种化合物在皮下剂量为100mg/kg时对氯仿诱导的快速性心律失常有一定保护作用，6种化合物在能保护80%或更多动物的剂量下未检测到毒性。对7种活性更强且无毒的衍生物在手术诱发心肌梗死的犬中进行了测试。所有这些衍生物在剂量远低于产生类似作用的利多卡因或妥卡尼剂量时，都产生了明显的抗心律失常作用。在犬中观察到的主要毒性作用是惊厥和心内传导抑制；它们通常发生在比产生抗心律失常作用更高的剂量下。几种化合物还能抑制麻醉犬中洋地黄诱导的心律失常。测定了三种化合物在犬中的半衰期和全身清除率；其中两种化合物的半衰期与在临床试验中作为长效口服活性抗心律失常药物的妥卡尼相当。
