SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS

描述（改编自申请人摘要）：理解和 包括惊恐障碍在内的病理性焦虑的治疗长期以来一直是一种 主要关注心理健康。 在最近的一项研究中， 据报道，患有恐慌症或恐慌症的人可能会 考虑或企图自杀的其他精神障碍患者， 严重抑郁症 3-10%的成年人患有恐慌症 在他们的生活中袭击。 苯二氮卓类药物（Bz）用于治疗这些 已经显示疾病表现出广谱的药理学作用， 功效包括抗惊厥、镇静催眠、肌肉松弛和 抗焦虑作用（2-11）。 尽管这些药物的临床效果 药物，需要选择性抗焦虑/抗惊厥药（10-12） 其没有肌肉松弛剂/共济失调和镇静剂的副作用， 苯二氮卓类 在这方面，我们实验室最近的结果（14，20） 很刺激 根据化学和计算机辅助分析的结果， 包括BzR的药效团， 已经定义了激动剂与反向拮抗剂。 更重要的是 8-炔属取代的咪唑并苯并二氮杂卓1a和2a已被证明 对Bz 5（α 5 β 2 γ 2）受体亚型的选择性高40-70倍， 而betaCCt 5对Bz 1的选择性高出20倍 （α 1 β 2 γ 2）受体亚型。 这些是最具选择性的配体 分别报道了α 5和α 1 BzR亚型，并作为 寻找BzR亚型特异性药物的先导化合物。 刚性和 半刚性（受约束）配体将用于开发试剂 对Bz 1（方案7、8、9和12）和Bz 5（方案4、5、6、10和11）具有选择性 受体亚型 我们的目标是开发出超过150个 对Bz 1或Bz 5受体亚型的选择性高出一倍，以便 确定哪种生物学功能由哪种亚型介导。 是 我认为Bz亚型选择剂提供了一个最好的机会， 开发抗焦虑选择性抗焦虑和抗惊厥药物， 影响，并了解复杂的生理过程介导 GABA/BzR受体离子通道。 这些位点的选择性配体 Bz 2（alpha 2）和Bz 3（alpha 3）以及Bz 4（D1）alpha 4和 将研究Bz 6（D1）α 6受体亚型。 表征 BzR受体在亚型水平的药理学对于 了解焦虑的生理过程，包括 恐慌症抽搐和睡眠障碍以及设计 选择性药物（激动剂）治疗这些疾病状态， 滥用潜力

DESCRIPTION (Adapted from applicant's abstract): The understanding and treatment of pathological anxiety including panic disorder 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 3-10% of the adult population suffer from panic attacks during their lives. The benzodiazepines (Bz) used to treat these diseases have been shown to exhibit a broad spectrum of pharmacologic efficacies including anticonvulsant, sedative-hypnotic, muscle-relaxant and anxiolytic effects (2-11). Despite the clinical effectiveness of these drugs, there is a need for selective anxiolytic/anticonvulsants (10-12) which are devoid of the myorelaxant/ataxic and sedative side effects of the benzodiazepines. In this regard recent results (14, 20) from our laboratory are exciting. Based on a chemical and computer-assisted analysis of the inclusive pharmacophore for the BzR, the pharmacophoric descriptors for agonist versus inverse antagonist have been defined. More importantly, the 8-acetylenic substituted imidazobenzodiazepines 1a and 2a have been shown to be 40-70 times more selective for Bz5 (alpha5beta2gamma2) receptor subtypes, while betaCCt 5 has been shown to be 20 times more selective for Bz1 (alpha1beta2gamma2) receptor subtypes. These are the most selective ligands ever reported for alpha5 and alpha1 BzR subtypes, respectively, and serve as lead compounds in the search for BzR subtype specific agents. Rigid and semi-rigid (constrained) ligands will be employed to develop agents selective for Bz1 (Schemes 7,8,9 and 12), and Bz5 (Schemes 4,5,6,10 and 11) receptor subtypes. The goal is to develop ligands that are more than 150 times more selective for either Bz1 or Bz5 receptor subtypes in order to determine which biological function(s) is mediated by which subtype. It is felt that Bz subtype selective agents provide one of the best opportunities to develop anxioselective anxiolytic and anticonvulsants devoid of side effects and to understand the complex physiological processes mediated by the GABA/BzR receptor ion channel. Once selective ligands for these sites are developed, Bz2 (alpha2) and Bz3 (alpha3) as well as Bz4 (D1) alpha4 and Bz6 (D1) alpha6 receptor subtypes will be investigated. Characterization of the pharmacology of BzR receptors at the subtype level is crucial for understanding the physiological processes which underlie anxiety, including panic disorder convulsions, and sleep disorders as well as the design of selective agents (agonists) to treat these disease states with decreased abuse potential.