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：
7627278
负责人：
KELVIN W. GEE
金额：
$ 17.21万
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/7627278
关键词：
Accounting Adverse effects Affect Allosteric Site Alprazolam American 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 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 Relative (related person)Research Rodent Rodent Model Rotarod Performance Test Sampling Screening procedure Sedation procedure Selective Serotonin Reuptake Inhibitor Sexual Dysfunction Site Sleeplessness Specific qualifier value Staging Structure Symptoms Testing Therapeutic Therapeutic Uses Time Weight Gain barbituric acid salt base drug discovery etafenoxine functional group gamma-Aminobutyric Acid improved in vivo interest loreclezole meetings neurosteroids novel novel therapeutics pre-clinical public health relevance 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）：广义焦虑症（GAD）是一个服务不足的治疗区域，通常，心理药理学中可行的药物靶标在严重的干旱状态。除苯二氮卓类药物（BZ）（例如地西epa）之外，很少有可行的替代方法用于治疗GAD。 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BZ的药物发现努力集中在对GABAA的化合物中的选择？亚基是因为激活特定吗？亚基可能会解释焦虑症的效果。例如，对？2/?? 3亚基的BZ选择性可能是抗焦虑而没有镇静的。这个概念尚未在临床上进行验证。与GABAA受体上新型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。一组特定的非Bz化合物在含有受体的2/3 gabaa亚基中引起更大的GABA活性相对于含有受体的受体？1个亚基在文献中已知，如曲酸酸酸，loreclezole，etifoxine和mefenamic act。这些化合物中的几种已经进行了临床试验和/或临床上可用。此外，这些化合物相对于BZs具有降低的镇静电势。在含有类似这些早期一代化合物的受体的1个亚基的活性最小或没有活性的化合物会引起镇静作用吗？我们已经开发了该实验室中的化合物，这些化合物的数量级比这一代年龄较大的？2/?? 3选择性调节剂更有效。这些？选择性启原酮在含有受体的1个亚基处的无活性最少。我们会描述启原剂及其SARS？亚基的选择性是及时识别新一代的抗焦虑药，这些抗焦虑药不对BZ受体作用，但保留了BZS的全部抗焦虑功效，但副作用较少。拟议的研究将鉴定高效力源自具有不同效力以激活含有受体的亚基。确定中枢神经系统渗透的药代动力学后，将在简单的镇静动物模型中测试候选化合物。拟议研究的完成将产生合适的候选人，这将是未来研究的主题，以充分表征体内药理学和作用部位，并最终的目的是开发一种新型药物来治疗焦虑症。公共卫生相关性：美国焦虑症的公共卫生费用估计为每年$ 42B。焦虑症是高度治疗的，但患有焦虑症的患者中只有三分之一接受治疗。拟议项目的重点是开发治疗剂，以增强焦虑症治疗的疗法短缺，这是一个服务不足的治疗区域，影响18岁以上的一般人群的3.1％。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Limited central side effects of a β-subunit subtype-selective GABAA receptor allosteric modulator.

β 亚基亚型选择性 GABAA 受体变构调节剂的有限中枢副作用。

DOI：
10.1177/0269881113507643
发表时间：
2014
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
0
作者：
Yoshimura,RyanF;Tran,MinhtamB;Hogenkamp,DerkJ;Johnstone,TimothyB;Xie,JenniferY;Porreca,Frank;Gee,KelvinW
通讯作者：
Gee,KelvinW