RIGID PROBES--MODELING SELECTIVE ANXIOLYTICS FOR BZR

包括恐慌在内的病理性焦虑的认识和治疗 长期以来，精神障碍一直是心理健康方面的首要问题。 在最近的一项研究中，据报道，患有惊恐障碍或 恐慌症发作与患者一样有可能考虑或企图自杀。 患有其他精神障碍，如重度抑郁症。从3%到10% 成年人一生中都会遭受恐慌症的折磨。这个 用于治疗这些疾病的苯二氮卓类药物(BZR)已被证明 显示出广泛的药理作用，包括 抗惊厥药(27)，镇静催眠药(27)，肌肉松弛药(28)，以及 不含肌松剂的抗焦虑/抗惊厥药(13)- 苯二氮卓类药物的镇静副作用(13，20，27，28)。它是 可想而知，这些抗焦虑药物也可能表现出 减少滥用的可能性，以及减少戒断症状。 在这方面，我们实验室最近的结果(15，16)是令人兴奋的。 药效团的化学和计算机辅助分析 BZR的激动剂已被处决(15)。在此模型的基础上，6- 合成了丙基醚(6PBC)(16)，并在小鼠体内进行了筛选。 这种新试剂被发现具有抗焦虑/抗惊厥活性， 但完全没有肌肉松弛/共济失调的作用 与苯二氮卓类药物一起发生。更重要的是，6 PBC(16) 完全拮抗安定的肌肉松弛作用 仍在产生缓解焦虑的效果。方案III-IX概述如下 刚性和半刚性配体，将准备定义确切的 激动剂结合域的空间尺寸(见图4-8) 亲油性区域，以及电子密度的重要性 Phi 1和Phi 2上的配体。这些试剂将被合成，然后 在体外和体内(小鼠/大鼠)测试它们的有效性。这个 生物数据和合成孔径雷达将被编程到E/S-390(SYBYL) 系统，以进一步定义激动剂的药效团。自.以来 主要目标是合成选择性抗焦虑/抗惊厥药物， 选择所需的空间维度和电子密度 激动剂的活性将被确定。这将是真正的一步。 在寻找选择性抗焦虑药物方面取得了进展。从本质上讲， 方案III-IX中描述的配体的计算机辅助设计， 这些碱基中的许多将表现出激动剂活性；我们的主要兴趣 在于那些能引起选择性激动剂活性的物质。 CoMFA分析(17，18)将在任何时候对这些后一种模拟执行 SAR/BIONIC是可用的。 在分子水平上对BZR进行表征对于 了解导致焦虑的生化机制(29)； 包括惊恐障碍(14)和抽搐27，以及设计 治疗这些疾病状态的选择性药物(激动剂)。它是 相信，上述研究的成功实施将具有深远的意义 在药物化学和神经生物学方面取得成效。

The understanding and treatment of pathological anxiety including panic disorders (14) have long been a prime concern in regard to mental health. In a recent study it was reported, people who suffer panic disorder or panic attacks are as likely to contemplate or attempt suicide as patients with other mental disorders such as major depression. From 3 to 10% of the adult population suffer from panic attacks during their lives. The benzodiazepines (BzR) used to treat these diseases have been shown to exhibit a broad spectrum of pharmacologic efficacies including anticonvulsant (27), sedative-hypnotic (27), muscle-relaxant (28), and anxiolytic/-anticonvulsants (13) which are devoid of the myorelaxant- sedative side effects of the benzodiazepines.(13,20,27,28). It is conceivable that these anxioselective anxiolytics might also exhibit decreased abuse potential, as well as reduced symptoms of withdrawal. In this regard, recent results(15,16) from our laboratory are exciting. A chemical and computer assisted analysis of the pharmacophore for agonists at the BzR has been executed(15). Based on this model the 6- propyl ether (6 PBC) (16) has been synthesized and screened in mice. This new agent was found to elicit anxiolytic/anticonvulsant activity, but was completely devoid (16) of the muscle relaxant/ataxic effects which occur with the benzodiazepines. More importantly, 6 PBC (16) completely antagonized the muscle relaxant effects of diazepam while still producing the anxiolytic effect. Outlined in Schemes III-IX are rigid and semi-rigid ligands which will be prepared to define the exact spatial dimensions of the agonist binding domain (see Figures 4-8) at lipophilic regions, as well as the importance of electron density on the ligands at phi 1 and phi 2. These agents will be synthesized and then tested in vitro and in vivo (mice/rats) for their efficacy. The biological data and SAR will be programmed into the E/S-390 (SYBYL) system to further define the pharmacophore for agonists. Since the principle goal is the synthesis of selective anxiolytic/anticonvulsants, the spatial dimensions and electron density required for selective agonist activity will be determined. This would constitute a real step forward in the search for selective anxiolytics. By the very nature of the computer-assisted design of the ligands depicted in Schemes III-IX, many of these bases will exhibit agonist activity; our principal interest lies in those which elicit a selective agonist profile of activity. CoMFA analysis (17,18) will be executed on these latter analogs whenever the SAR/biology is available. Characterization of the BzR at the molecular level is crucial for understanding the biochemical mechanisms which underlie anxiety (29), including panic disorders (14), and convulsions 27, as well as the design of selective agents (agonists) to treat these disease states. It is believed, the successful execution of the above studies will have far reaching effects in medicinal chemistry and neurobiology.