Non-sedating modulators of GABA-A receptors for anxiety

GABA-A 受体的非镇静调节剂治疗焦虑

基本信息

批准号：
7532486
负责人：
KELVIN W. GEE
金额：
$ 17.75万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7532486
关键词：
Accounting Adverse effects Affect Allosteric Site Alprazolam American Aminobutyric Acid Aminobutyric Acids Amnesia Animal Model Anti-Anxiety Agents Anticonvulsants Antidepressive Agents Anxiety Anxiety Disorders Area Barbiturates Benzodiazepine Receptor Benzodiazepines Binding Biological Availability Brain Cell Nucleus Chloride Channels Class Clinical Clinical Trials Complex Data Development Diazepam Disadvantaged Dose Droughts Drug Delivery Systems Drug Kinetics Drug usage Future GABA-A Receptor General Population Generalized Anxiety Disorder Generations Goals Health Care Costs Isomerism Laboratories Lead Ligands Literature Measures Mediating Medical Mefenamic Acid Memory Loss Mind Modeling Modification Mus Muscle Neuraxis Neurotransmitters Oral Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacology Plasma Property Psychopharmacology Public Health Range Relative (related person)Rodent Rodent Model Rotarod Performance Test Sampling Screening procedure Sedation procedure Selective Serotonin Reuptake Inhibitor Sexual Dysfunction Site Sleeplessness Specific qualifier value Staging Steroids Structure Symptoms Testing Therapeutic Therapeutic Uses Time Week Weight Gain barbituric acid salt base concept drug discovery etafenoxine functional group gamma-Aminobutyric Acid improved in vivo interest loreclezole novel novel therapeutics pre-clinical receptor research clinical testing research study response sedative tracazolate

项目摘要

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.

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，其中精神药理学中可行的药物靶点总体上处于严重干旱状态。除了苯二氮卓类 (BZ)（如地西泮）之外，几乎没有其他可行的替代药物可用于治疗广泛性焦虑症。 BZ 对 GAD 的临床用途受到镇静、记忆丧失等副作用的严重限制。因此，改善 BZ 的药物发现工作集中在对 GABAA 选择性的化合物上。亚单位因为特定的激活？亚基可能会产生抗焦虑选择性效应。例如，对α2/β3亚基具有选择性的BZ可以具有抗焦虑作用而无需镇静作用。这个概念还有待临床验证。与 GABAA 受体上的新变构位点结合的化合物可能以优于 BZ 的方式调节 GABA 的作用。文献中已知一组特定的非BZ化合物，其在含有α2/β3GABAA亚基的受体中相对于含有α1亚基的受体引发更高的GABA活性，如曲卡唑酯、洛来克唑、依替福辛和甲芬那酸。其中一些化合物已经通过了临床试验和/或可用于临床。此外，与 BZ 相比，这些化合物的镇静作用较低。像这些早期化合物这样的含有受体的 ?1 亚基活性极低或没有活性的化合物是否不太可能引起镇静作用？我们在该实验室开发了比老一代 β2/β3 选择性调节剂强几个数量级的化合物。这些？选择性烯胺酮对含有受体的α1亚基表现出极小的活性或没有活性。我们将描述烯胺酮及其 SAR 的特征？亚基选择性作为鉴定新一代抗焦虑药的及时第一步，该抗焦虑药不作用于 BZ 受体，但保留了 BZ 的全部抗焦虑功效，但副作用较少。拟议的研究将鉴定具有不同功效的高效烯胺酮，以激活含有受体的α1亚基。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一个合适的候选药物，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 $42B。焦虑症是可以治愈的，但只有大约三分之一的焦虑症患者接受了治疗。该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，焦虑症是一个服务不足的治疗领域，影响着 18 岁以上人群的 3.1%。