Non-sedating modulators of GABA-A receptors for anxiety

描述（由申请人提供）：广泛性焦虑障碍（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（BZs），如地西泮，很少有可行的替代品用于治疗广泛性焦虑症。bz治疗广泛性焦虑症的临床应用受到副作用的严重限制，如镇静、记忆丧失等。因此，改善bz的药物发现工作集中在选择性GABAA ？亚基因为激活特异性？亚单位可以解释焦虑选择效应。例如，bz对？2/?？3个亚单位可能具有抗焦虑作用，无需镇静。这一概念尚未得到临床验证。结合GABAA受体上新的变构位点的化合物可能以优于bz的方式调节GABA的作用。一组特殊的非bz化合物，在？2/?？含GABAA亚基的受体与含？文献中已知有1个亚基，如曲唑酸、罗来唑、依替辛和甲氧胺酸。其中一些化合物已经通过临床试验和/或临床可用。此外，这些化合物的镇静潜力相对于BZs有所降低。活性极低或无活性的化合物在？含有像这些早期化合物的受体的亚基不太可能引起镇静作用？我们在实验室开发的化合物比老一代的？2/?？3个选择性调制器。这些吗?选择性胺酮在？含有受体的亚基。我们将对胺酮及其SARs进行表征。亚基选择性是鉴定新一代抗焦虑药的及时的第一步，这些抗焦虑药不作用于BZ受体，但保留了BZ的全部抗焦虑功效，但副作用更少。拟议的研究将确定具有不同功效的高效胺酮来激活？含有受体的亚基。在确定中枢神经系统渗透的药代动力学后，将在简单的镇静和焦虑动物模型中测试候选化合物。完成拟议的研究将产生合适的候选药物，这些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了治疗。拟议项目的重点是开发治疗方法，以弥补焦虑症治疗方法的不足，这是一个服务不足的治疗领域，影响了3.1%的18岁以上的普通人群。

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.