B-CARBOLINES: SEARCH FOR VALIUM AGONISTS & ANTAGONISTS

纵观历史，病理性或过度焦虑显然是 被指定为不受欢迎的，并了解是起源和治疗 是一个主要问题。 用于治疗焦虑的苯二氮卓类药物是一种 作为抗焦虑药具有广泛治疗应用的一类化合物， 抗惊厥药、催眠药和肌肉松弛药。 虽然这些代理商 在疾病状态的治疗中极其重要，其确切机制 行动仍然存在争议。 最近有报道称， 3-乙氧基羰基-β-咔啉（2），3-甲氧基羰基-β-咔啉（1）， 3-叔丁氧羰基-β-咔啉（3）和3-羟甲基-β-咔啉（4） 所有药物均有效抑制[3 H]地西泮与苯二氮卓类受体的结合， 拮抗安定的抗惊厥作用。 更重要的是在 与“纯”苯二氮卓类拮抗剂R 015 -1788相比， 在我们的实验室中，β-咔啉已被证明具有内在的 他们自己的影响，相反的苯二氮卓类，和 每种化合物的效果不同。 例如，（1）被证明是一个 惊厥药，（2）一种促惊厥药（猴子中的焦虑药），（4）增加 睡眠潜伏期，减少大鼠的总睡眠和非REM睡眠，而不影响 抽搐，而叔丁酯（3）是第一个β-咔啉， 在体内发挥部分激动剂/拮抗剂活性。 在这种情况下，不同 一系列3-羟甲基-、3-烷基酮基-和3-烷氧基羰基-取代的 β-咔啉将在体外合成和测试（突触体 膜）和体内（小鼠，大鼠，猴子），以确定什么结构 对于强效选择性、拮抗剂或激动剂， 活性; 3-烷基酮基化合物是重要的，因为它们不能被 代谢为无活性酸（5）。 由于报告的影响， β-咔啉与R 015 -1788报告的不同，烷基化 将制备基于β-咔啉结构的试剂来标记 苯二氮卓受体的推定拮抗剂位点和数据 与苯二氮卓类不可逆抑制剂irazepine相比， 肯纳卓。 从上述实验中获得的知识将：1）导致 选择性苯并二氮杂拮抗剂和非苯并二氮杂拮抗剂的制备 激动剂，2）确定β-咔啉是否与相同的受体结合 与苯二氮卓类一样，3）确定苯二氮卓类是否 受体参与睡眠的生理控制（3 HMC工作）， 4)更好地了解与这些疾病相关的生理过程 或受苯二氮卓受体复合物调节。 此外，克 将制备大量的1-4的类似物并在体内筛选， 分离出β-咔啉的内在效应， 特异性地与一种Bz受体亚型相互作用， 另

Throughout history pathological or excessive anxiety has been clearly designated as undesirable and the understanding of is origin and treatment are a major concern. The benzodiazepines employed to treat anxiety are a group of compounds with wide therapeutic application as anxiolytics, anticonvulsants, hypnotics and muscle relaxants. Although these agents are extremely important in treatment of disease states, their exact mechanism of action remains controversial. Recently it has been reported that 3-ethoxycarbonyl-Beta-carboline(2), 3-methoxycarbonyl-Beta-carboline(1), 3-t-butoxycarbonyl-Beta-carboline(3), and 3-hydroxymethyl-Beta-carboline(4) all potently inhibit [3H] diazepam binding to benzodiazepine receptors and antagonize the anticonvulsant effects of diazepam. More importantly, in contrast to the "pure" benzodiazepine antagonist R015-1788, these Beta-carbolines have been shown, in our laboratories, to possess intrinsic effects of their own, opposite to those of the benzodiazepines, and the effect is different for each compound. For example, (1) was shown to be a convulsant, (2) a proconvulsant (anxiogenic in monkeys), (4) increased sleep latency, reduced total and non-REM sleep in rats without effecting convulsions, while the t-butyl ester(3) was the first Beta-carboline to exert partial agonist/antagonist activity in vivo. In this vein, different series of 3-hydroxymethyl-, 3-alkylketo-, and 3-alkoxycarbonyl-substituted Beta-carbolines will be snythesized and tested in vitro (synaptosomal membranes) and in vivo (mice, rats, monkeys) to determine what structural requiremens are necessary for potent selective, antagonist or agonist activity; the 3-alkylketo compounds are important for they cannot be metabolized to the inactive acid(5). Since the effects reported for Beta-carbolines are different from those reported for R015-1788, alkylating agents based on the structure of Beta-carbolines will be prepared to label the putative antagonist site(s) of benzodiazepine receptors and data compared to that for benzodiazepine irreversible inhibitors irazepine and kenazepine. Knowledge gained from the above experiments will: 1) result in preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether Beta-carbolines bind to the same receptor site(s) as do benzodiazepines, 3) determine whether benzodiazepine receptors are involved in the physiologic control of sleep (3HMC work), and 4) provide a better understanding of the physiological processes related to, or regulated by the benzodiazepine receptor complex. In addition, gram quantities of analogs of 1-4 will be prepared and screened in vivo to separate out the intrinsic effects of Beta-carbolines, and to design agents specific for interaction with one Bz receptor subtype in preference to another.