RIGID PROBES: MODELING SELECTIVE ANXIOLYTICS FOR BZR

病理性焦虑包括惊恐的认识和治疗 长期以来，精神障碍一直是精神健康方面的主要关注点。 在最近的一项研究中，据报道，患有恐慌症或 恐慌症患者有可能考虑或企图自杀， 其他精神疾病如重度抑郁症。 从3%到10% 成年人在他们的一生中遭受惊恐发作。 的 用于治疗这些疾病的苯二氮卓类药物（BzR）已被证明 表现出广泛的药理学功效，包括 抗惊厥药（27）、镇静催眠药（27）、肌肉松弛药（28），以及 抗焦虑/抗惊厥药（13），其不含肌松弛剂， 苯二氮卓类药物的镇静副作用(13，20，27，28）。 是 可以想象，这些抗焦虑选择性抗焦虑药也可能表现出 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）令人兴奋。 药效团的化学和计算机辅助分析 BzR激动剂已被执行（15）。基于此模型，6- 丙醚（6 PBC）（16）已合成并在小鼠中筛选。 发现这种新药具有抗焦虑/抗惊厥活性， 但完全没有肌肉松弛/共济失调作用 苯二氮卓类药物也会出现这种情况更重要的是，6个PBC（16） 完全拮抗地西泮的肌松作用， 仍能产生抗焦虑作用 方案III-IX中概述的是 刚性和半刚性配体，其将被制备以定义精确的 激动剂结合结构域的空间尺寸（参见图4-8）， 亲脂性区域，以及电子密度的重要性 在phi 1和phi 2处的配体。 这些药剂将被合成， 在体外和体内（小鼠/大鼠）测试它们的功效。 的 生物数据和SAR将被编程到E/S-390（SYBYL）中 系统，以进一步定义激动剂的药效团。 以来 主要目标是合成选择性抗焦虑/抗惊厥药， 空间尺寸和电子密度所需的选择 将测定激动剂活性。 这将是一个真实的步骤 在寻找选择性抗焦虑药方面取得了进展。 由于...的本质 计算机辅助设计方案III-IX中描述的配体， 这些碱基中的许多将表现出激动剂活性;我们的主要兴趣是 在于引发选择性激动剂活性的那些。 CoMFA分析（17，18）将在这些后一种类似物上执行， SAR/生物学可用。 在分子水平上表征BzR对于以下方面至关重要： 了解焦虑的生化机制（29）， 包括惊恐障碍（14）和抽搐27，以及设计 选择性药物（激动剂）来治疗这些疾病状态。 是 相信，上述研究的成功实施将对我们的未来产生深远的影响。 在药物化学和神经生物学中发挥作用。

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.