Non-sedating modulators of GABA-A receptors for anxiety

GABA-A 受体的非镇静调节剂治疗焦虑

• 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
• 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

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)是一个治疗服务不足的领域，精神药理学中可行的药物靶点一般处于严重的干旱状态。除了苯二氮卓类(BZS)之外，几乎没有其他可行的替代药物，如安定，用于治疗广泛性焦虑症。BZS治疗广泛性AD的临床应用受到镇静、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选择性GABAA？亚基是因为激活了特定的？亚基可能解释了焦虑选择效应。例如，对？2/？3亚基有选择性的BZS可能在没有镇静的情况下具有抗焦虑作用。这一概念还有待临床验证。与GABAA受体上新的变构位点结合的化合物可能以一种优于BZS的方式调节GABA的作用。文献中已知一类非BZ类化合物在含有受体的？2/？3 GABAA亚基中比含有？1亚基的受体具有更高的GABA活性，如曲唑醇、洛雷克唑、替福辛和甲芬酸。这些化合物中有几个已经进行了临床试验和/或临床可用。此外，与BZS相比，这些化合物具有更低的镇静潜力。像这些早期化合物一样，含有受体的？1亚基活性极低或没有活性的化合物不太可能产生镇静作用？我们在这个实验室中开发出的化合物比老一代？2/？3选择性调节剂的效力高几个数量级。这些？选择性氨基酮类在含有受体的？1亚基上表现出极小的或没有活性。我们将描述氨基酮类药物及其SARS的特征。亚基选择性作为鉴定新一代不作用于BZ受体的抗焦虑药物的及时的第一步，仍然保留了BZS的全部抗焦虑效果，但副作用更少。拟议的研究将确定具有不同功效的高效烯丙酮，以激活含有？1亚单位的受体。在确定中枢神经系统渗透的药代动力学后，候选化合物将在镇静和焦虑的简单动物模型中进行测试。拟议研究的完成将产生一位合适的候选人(S)，该候选人将成为未来研究的主题，以全面描述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(S)。公共卫生相关性：据估计，美国每年因焦虑症造成的公共卫生成本为420亿美元。焦虑症是高度可治疗的，然而只有大约三分之一的焦虑症患者得到了治疗。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短缺，焦虑症是一个服务不足的治疗领域，影响着3.1%的18岁以上总人口。

项目成果

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)
• 作者: Yoshimura,RyanF;Tran,MinhtamB;Hogenkamp,DerkJ;Johnstone,TimothyB;Xie,JenniferY;Porreca,Frank;Gee,KelvinW
• 通讯作者: Gee,KelvinW