BETA-CARBOLINES: VALIUM AGONISTS AND ANTAGONISTS

纵观历史，病理性或过度焦虑一直是 明确指出，不可取的，并了解其 来源和治疗是一个主要问题。 苯二氮卓类（Bz） 用于治疗焦虑的是一组化合物， 作为抗焦虑药、抗惊厥药、催眠药的治疗应用 和肌肉松弛剂6，7. 这些代理人现在被认为是在发挥他们的 通过GABA/Bz/C1复合物的生理效应2，45. 最近， 一系列刚性的平面二氢吡啶并二吲哚已经被 在我们的实验室合成，并显示出强大的 体外对苯二氮卓受体（BzR）的亲和力（5 nM）17. 母体化合物2（X = H）显示出反向激动剂活性， vivo 17. 此外，2-甲氧基类似物4e是有效的 促惊厥药，而2-氯类似物4d显示拮抗剂 活性17类似于Ro 15 - 1788。 人们觉得这些严格的类比 可能符合一个受体亚位点，但不能 在构象上旋转21，61，以结合第二亚型。 在 除了增强的Bz 1或Bz 2选择性之外，这些刚性平面， 将采用活性配体来模拟BzR的药效团。 基于这些电极导线，不同系列的刚性4、7、10和 半刚性8，9类似物将在体外合成和测试 （突触体膜）和体内（小鼠、大鼠、猴）， 确定什么样的结构要求是必要的， 选择性（Bz1或Bz2）反向激动剂、拮抗剂或激动剂 活性;吡啶并二吲哚4是重要的，因为它们应该 在体内具有长半衰期。 由于观察到的影响， β-咔啉12、2和4e17与报道的不同 对于Ro 15 - 1788 15，基于这些β- 将制备咔啉类似物以标记"建议的" 32、59、60 离散的反向激动剂/拮抗剂受体位点。 信息 从上述研究中获得的信息将：1）导致编制 选择性苯二氮拮抗剂和非苯二氮 激动剂，2）确定β-咔啉是否结合到 与苯二氮卓类相同的受体位点，3）决定 苯二氮卓受体对焦虑的影响4，9，22，23，睡眠，28 结论27和记忆29通过提供更好的理解 GABA/Bz/C1复合物影响的生理过程 两点四十五分 此外，与4，7， 8、9和10将在体内制备和筛选以分离出 β-咔啉的内在效应，并设计代理 优先与一种Bz受体亚型特异性相互作用 到另

Throughout history pathological or excessive anxiety has been clearly designated as undesirable and the understanding of its origin and treatment are a major concern. The benzodiazepines (Bz) employed to treat anxiety are a group of compounds with wide therapeutic applications as anxiolytics, anticonvulsants, hypnotics and muscle relaxants 6,7. These agents are now felt to exert their physiological effects via the GABA/Bz/C1 complex 2,45. Recently, a series of rigid, planar dihydropyridodiindoles have been synthesized in our laboratory and shown to demonstrate potent affinity (5 nM) for benzodiazepine receptors (BzR) in vitro 17. The parent compound 2 (X=H) exhibited inverse agonist activity in vivo 17. Moreover, the 2-methoxy analog 4e was a potent proconvulsant, while the 2-chloro analog 4d demonstrated antagonist activity 17 similar to Ro 15-1788. It is felt these rigid analogs may conform to one receptor subsite, but will not be able to rotate, conformationally 21,61, to bind to a second subtype. In addition to enhanced Bz1 or Bz2 selectivity, these rigid planar, active ligands will be employed to model the pharmacophore for BzR. Based on these leads, different series of rigid 4, 7, 10, and semirigid 8, 9 analogs will be synthesized and tested in vitro (synaptosomal membranes) and in vivo (mice, rats, monkeys) to determine what structural requirements are necessary for potent selective (Bz1, or Bz2) inverse agonist, antagonist or agonist activity; the pyridodiinodoles 4 are important for they should possess long half-lives in vivo. Since the effects observed for beta-carbolines 12, 2 and 4e17 are different from those reported for Ro 15-1788 15, irreversible inhibitors based on these beta- carboline analogs will be prepared to label the "proposed" 32,59,60 discrete inverse agonist/antagonist receptor site. Information gained from the above studies will: 1) result in preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether or not beta-carbolines bind to the same receptor sites(s) as do benzodiazepines, 3) determine the effect of benzodiazepine receptors on anxiety 4,9,22,23, sleep, 28 conclusions 27, and memory 29 by providing a better understanding of the physiological processes influenced by the GABA/Bz/C1 complex 2, 45. In addition, gram quantities of analogs related to 4, 7, 8, 9, and 10 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.