Polyalkylpiperidines: a New Series of Ganglion-blocking Agents
Polyalkylpiperidines: a New Series of Ganglion-blocking Agents
复制标题
聚烷基哌啶：一系列新的神经节阻滞剂
作者：
A. Spinks;E. Young
1956年，Stone、Torchiana、Navarro和Beyer1发现，仲胺3-甲氨基异辛烷(甲基胺)具有强大的神经节阻滞性，到目前为止只在季碱中表现出来；此后再没有类似的描述。对氮原子被烷基紧密包围的各种仲基和叔基的研究表明，许多聚烷基哌啶(英国专利申请第4905/57、4906/57和4907/57号)作为神经节阻滞剂和降压剂具有高度的活性。在所研究的一大系列化合物中，最有希望的是1：2：2：6：6-五甲基哌啶(I；R=R1=R2=R3=R4=Me)和1-乙基-2：2：6：6-四甲基哌啶(I；R=ET；R1=R2=R3=R4=Me)。这些化合物和相关化合物在氯醛糖麻醉的猫身上进行了静脉测试，以确定它们是否有能力阻止神经节前对瞬膜的刺激。通过本试验，五甲基化合物的效力约为2.5倍，乙基四甲基化合物的效力约为甲氨基甲胺的3.0倍，三种药物的作用时间相似，单次剂量为0.2mg./kgm。乙基化合物在大约两小时内具有可察觉的效果。这两种化合物都能阻断对苯二甲基哌嗪、颈动脉阻塞和内脏传出刺激的升压反应，在阿托品化的猫中，对乙酰胆碱的升压反应，在0.1-0.2mg./kgm剂量后，所有这些作用都令人印象深刻。两种药物中的一种。该药可阻断苯二甲基哌嗪在体外引起的豚鼠回肠收缩，降低小鼠体内肠道动力，降低大鼠胃液自发分泌率。在最后一次试验中，1：2：2：6：6-五甲基哌啶的效力是甲乙基哌啶的两倍，1-乙基-2：2：6：6-四甲基哌啶的效力是甲氨基甲胺的三倍，这三种药物都是皮下给药。
IN 1956 Stone, Torchiana, Navarro and Beyer1 discovered that powerful ganglion-blocking properties, hitherto demonstrated only in quaternary bases, were possessed by the secondary amine 3-methylaminoisocamphane (mecamylamine); nothing comparable has since been described. A study of a variety of secondary and tertiary bases in which the nitrogen atom is closely surrounded by alkyl groups has now shown that many polyalkylpiperidines (U.K. Patent Applications Nos. 4905/57, 4906/57 and 4907/57) are highly active as ganglion-blocking and hypotensive agents. The most promising of a large series examined were 1 : 2 : 2 : 6 : 6-pentamethylpiperidine (I; R = R1 = R2 = R3 = R4 = Me) and 1-ethyl-2 : 2 : 6 : 6-tetramethylpiperidine (I; R = Et; R1 = R2 = R3 = R4 = Me). These and related compounds were tested intravenously in the cat, anaesthetized with chloralose, for their ability to block preganglionic stimulation of the nictitating membrane. By this test, the pentamethyl compound was about 2.5 and the ethyl tetramethyl compound about 3.0 times as potent as mecamylamine and the effects of all three drugs were of similar duration, a single dose of 0.2 mgm./kgm. of the ethyl compound having a perceptible effect for approximately two hours. Both compounds also block the pressor response to phenyldimethylpiperazinium, carotid occlusion, and efferent splanchnic stimulation, and, in the atropinized cat, to acetyl choline, all these actions being impressive after doses of 0.1–0.2 mgm./kgm. of either drug. The drugs block the contraction of the guinea pig ileum, elicited in vitro by phenyldimethylpiperazinium, reduce intestinal motility in vivo as judged by rate of excretion of fæces by mice, and reduce the rate of spontaneous secretion of gastric juice in the rat. By the last test 1 : 2 : 2 : 6 : 6-pentamethylpiperidine is twice, and 1-ethyl-2 : 2 : 6 : 6-tetramethylpiperidine three times as potent as mecamylamine when all three drugs are given subcutaneously.