SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS

说明(改编自申请人的摘要)：理解和 长期以来，包括惊恐障碍在内的病理性焦虑的治疗一直是 在精神健康方面最令人关切的问题。在最近的一项研究中， 据报道，患有恐慌症或恐慌症发作的人 像患有其他精神障碍的患者一样考虑或试图自杀 作为严重的抑郁症。3%-10%的成年人患有恐慌症 在他们有生之年遭受袭击。用于治疗这些疾病的苯二氮卓类药物(BZ) 疾病已被证明具有广泛的药理作用。 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很好 药物方面，需要有选择性的抗焦虑/抗惊厥药物(10-12) 它们没有肌松药/共济失调和镇静的副作用 苯二氮卓类。在这方面，我们实验室的最新结果(14，20) 是令人兴奋的。基于化学和计算机辅助分析 BZR的包含性药效团，药典描述符 对激动剂和反向拮抗剂进行了定义。更重要的是， 8-乙炔取代的咪唑苯并二氮杂环化合物1a和2a已被证明 对Bz5(Alpha5β2 Gamma2)受体亚型的选择性提高40-70倍， 而BetaCCT 5对Bz1的选择性是Bz1的20倍 (α1β2γ2)受体亚型。这些是最具选择性的配体 曾经分别报道过alpha5和alpha1 BZR亚型，并用作 寻找BZR亚型特异性药物的先导化合物。刚性和 半刚性(受约束的)配体将被用于开发试剂 选择Bz1(方案7、8、9和12)和Bz5(方案4、5、6、10和11) 受体亚型。目标是开发出150个以上的配体 对Bz1或Bz5受体亚型的选择性更高，以便 确定哪个生物学功能(S)是由哪个亚型介导的。它是 我觉得BZ亚型选择性药物提供了最好的机会之一 开发不含副作用的抗焦虑和抗惊厥药物 并了解其介导的复杂的生理过程 GABA/BZR受体离子通道。曾经是这些位点的选择性配体 Bz2(Alpha2)和Bz3(Alpha3)以及Bz4(D1)alpha4和 Bz6(D1)α6受体亚型将被研究。特征描述 BZR受体在亚型水平的药理学对于 了解导致焦虑的生理过程，包括 惊恐障碍、抽搐和睡眠障碍以及 治疗这些疾病状态的选择性药物(激动剂) 滥用的可能性。

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.