B-CARBOLINES: SEARCH FOR VALIUM AGONISTS & ANTAGONISTS

纵观历史，病态的或过度的焦虑显然 被认为是不可取的，并且对IS的起源和治疗 是一个主要的担忧。用于治疗焦虑的苯二氮卓类药物是一种 一组具有广泛治疗应用的化合物，作为抗焦虑药物， 抗惊厥药、催眠药和肌肉松弛药。尽管这些特工是 在疾病状态的治疗中极其重要，它们的确切机制 行动的方式仍然存在争议。最近有报道说， 3-乙氧基甲酰基-β-卡宾(2)，3-甲氧基乙基-β-卡宾(1)， 3-叔丁氧基-β-卡宾(3)和3-羟甲基-β-卡宾(4) 都能有效地抑制[~3H]地西潘与苯二氮卓类受体的结合，并 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R015-1788相比，这些 在我们的实验室中，β-碳氢化合物已被证明具有内在的 它们自身的作用，与苯二氮卓类药物相反，而且 每种化合物的效果都不同。例如，(1)被证明是一个 惊厥药，(2)前惊厥药(在猴子中会引起焦虑)，(4)增加 睡眠潜伏期、总睡眠和非快速眼动睡眠减少而不影响 惊厥，而叔丁酯(3)是第一个 在体内发挥部分激动剂/拮抗剂活性。在这个脉络中，不同的 3-羟甲基、3-烷基酮和3-烷氧基取代的系列化合物 β-Caroline将被筛选并在体外进行测试(突触体 膜)和体内(小鼠、大鼠、猴子)来确定什么结构 对于有效的选择性、拮抗剂或激动剂是必需的 活性；3-烷基酮类化合物很重要，因为它们不能 代谢成无活性的酸(5)。由于报告的影响 β-碳氢化合物不同于R015-1788的报道，烷基化 将制备基于Beta-Caroline结构的试剂来标记 苯二氮卓类受体的可能拮抗部位(S)及数据 与苯二氮类不可逆抑制剂伊拉西平和伊拉西平相比 凯那西平。从上述实验中获得的知识将：1)导致 选择性苯二氮卓类拮抗剂和非苯二氮卓类药物的制备 激动剂，2)决定Beta-Caroline是否与同一受体结合 现场(S)做苯二氮卓类药物，3)测定苯二氮卓类药物 受体参与睡眠的生理控制(3HMC工作)，以及 4)更好地了解相关的生理过程 与苯二氮卓类受体复合体结合，或受其调节。此外，葛兰克 将在体内制备和筛选大量的1-4类似物，以 分离出Beta-Caroline的内在影响，并设计试剂 特异性地与一个BZ受体亚型相互作用 又一个。

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.