Non-sedating modulators of GABA-A receptors for anxiety

描述（由申请人提供）：广泛性焦虑症（GAD）是一个服务不足的治疗领域，在精神药理学中，可行的药物靶点通常处于严重的干旱状态。除了苯二氮卓类药物（BZ）（如地西泮）外，很少有可行的替代品用于治疗广泛性焦虑症。BZs对GAD的临床实用性受到镇静、记忆丧失等副作用的严重限制。因此，改善BZs的药物发现努力集中在GABAA选择性化合物上。亚单位，因为激活特定的？亚基可以解释抗焦虑选择性效应。例如，BZs选择性的？2/？？3亚单位可能是抗焦虑的，而没有镇静作用。这一概念尚待临床验证。与GABAA受体上新的变构位点结合的化合物可能以比BZ更上级的方式调节GABA的作用。一组特殊的非BZ化合物，引起更大的GABA活性？2/？？3含GABAA亚单位的受体相对于含？1亚基在文献中是已知的，如曲唑酯、loreclezole、艾提伏辛和甲芬那酸。这些化合物中的几种已经通过临床试验和/或临床上可用。此外，这些化合物相对于BZ具有降低的镇静潜力。化合物是否具有最小活性或无活性？1亚基含有受体像这些早期的一代化合物不太可能导致镇静作用？我们在这个实验室里已经开发出了比老一代药物更有效的化合物。2/？？3选择性调节剂。这些吗？选择性烯胺酮在？1个亚单位。我们将描述烯胺酮和它们的SAR？亚基选择性作为鉴定新一代抗焦虑药的及时的第一步，所述新一代抗焦虑药不作用于BZ受体，但保留BZ的全部抗焦虑功效，但副作用较少。拟议的研究将确定具有不同功效的高效烯胺酮，以激活？1个亚单位。在确定CNS渗透的药代动力学后，将在镇静和焦虑的简单动物模型中测试候选化合物。完成拟定研究将产生一种合适的候选药物，该候选药物将成为未来研究的主题，以充分表征体内药理学和作用部位，最终目标是开发一种治疗焦虑症的新药。公共卫生相关性：美国焦虑症的公共卫生成本估计为每年420亿美元。焦虑症是高度可治疗的，但只有大约三分之一的焦虑症患者接受治疗。拟议项目的重点是开发治疗方法，以弥补治疗焦虑症的疗法不足，这是一个服务不足的治疗领域，影响到18岁以上总人口的3.1%。

DESCRIPTION (provided by applicant): Generalized anxiety disorder (GAD) is an underserved therapeutic area where viable drug targets in psychopharmacology in general are in a severe state of drought. Few viable alternatives other than benzodiazepines (BZs), like diazepam, are used for the treatment of GAD. The clinical usefulness of the BZs for GAD is severely limited by side effects such as sedation, memory loss, etc. Therefore, drug discovery efforts to improve BZs have focused on compounds selective for GABAA ? subunits because activation of specific ? subunits may account for anxioselective effects. For example, BZs selective for the ?2/??3 subunit may be anxiolytic without sedation. This concept is yet to be clinically validated. Compounds that bind to novel allosteric sites on the GABAA receptor might modulate the action of GABA in a manner superior to BZs. A particular group of non-BZ compounds that elicit greater GABA activity in ?2/??3 GABAA subunit containing receptors relative to receptors containing ?1 subunits are known in the literature like tracazolate, loreclezole, etifoxine and mefenamic acid. Several of these compounds have gone through clinical trials and/or are clinically available. Moreover these compounds have a reduced sedative potential relative to BZs. Are compounds with minimal or no activity at ?1 subunit containing receptors like these early generation compounds less likely to cause sedative effects? We have developed compounds in this laboratory that are several orders of magnitude more potent than this older generation of ?2/??3 selective modulators. These ? selective enaminones show minimal to no activity at ?1 subunit containing receptors. We will characterize enaminones and their SARs for ? subunit selectivity as a timely first-step in the identification of a new generation of anxiolytics that do not act at the BZ receptor yet retain the full anxiolytic efficacy of the BZs but with fewer side effects. The proposed studies will identify high potency enaminones with varying efficacies to activate ?1 subunit containing receptors. Candidate compounds will be tested in simple animal models of sedation and anxiety after pharmacokinetics of CNS penetration are determined. Completion of the proposed studies will yield a suitable candidate(s) that will be the topic of future studies to fully characterize in vivo pharmacology and site of action, with the ultimate goal of developing a novel drug(s) for the treatment of anxiety disorders. The Public Health Relevance: The US public health costs of anxiety disorders are estimated to be $42B a year. Anxiety disorders are highly treatable, yet only about one-third of those suffering from an anxiety disorder receive treatment. The focus of the proposed project is to develop therapeutics to bolster the shortfall of therapies for the treatment of anxiety disorders, an underserved therapeutic area that affects 3.1% of the general population over 18.