MICA: Valium without the sedation: Non-sedating anxiolytic GABAA receptor modulators for the treatment of anxiety disorders.

该提案旨在开发非镇静抗焦虑药物（“无镇静作用的安定”），这将代表50多年来焦虑症治疗的首次重大进展。焦虑症是患者访问他们的GP的最常见原因，其中广泛性焦虑症（GAD）是最普遍的。它影响了大约5%的人口在他们的生活中的某个时候，其特点是持续的，普遍的和过度的担忧。因此，它是一种使人衰弱的疾病，对社会的影响相当于抑郁症，每年花费英国100亿英镑。由于各种原因，目前对GAD的治疗并不令人满意，自20世纪60年代初引入苯二氮卓类药物以来，一直没有重大创新。苯二氮卓类药物是一类所谓的次要镇静剂药物，其中最着名的是安定（安定，又名“母亲的小帮手”）。苯二氮卓类药物可有效减轻焦虑（即，它们是抗焦虑药），但镇静是主要的副作用。直到最近，所有试图确定下一代药物的“拨号”这些副作用，特别是镇静，一直没有成功。然而，随着我们对苯二氮卓类药物如何发挥作用的认识的最新进展，我们现在能够了解开发非镇静抗焦虑药所需的条件，更重要的是，我们如何识别此类药物。这一建议旨在利用我们知识中的这些突破。 苯二氮卓类药物通过改变大脑中一种叫做γ-氨基丁酸（GABA）的化学物质（神经递质）的作用来发挥作用。这种神经递质与大脑中的四种类似蛋白质结合，称为α 1，α 2，α 3和α 5 GABAA受体（GABAAR）。最近的数据表明，α 1亚型负责镇静作用，因此，假设通过特异性地影响α 2和α 3（"抗焦虑"）GABAAR亚型，同时避免α 1（"镇静"）亚型，应该可以鉴定出非镇静作用的抗焦虑化合物。这一假设被证明是正确的，许多动物实验表明GABAAR α 2/α 3药物确实是一种非镇静抗焦虑药，早期的人体研究也支持这一假设。由于许多与其作用机制无关的原因，先前在人体中测试的GABAAR α 2/α 3药物不再被开发，因此我们希望继续这一领域的研究并开发新的GABAAR α 2/α 3药物，这些药物有可能彻底改变焦虑症的治疗，特别是GAD。

This proposal aims to develop non-sedating anxiolytic drugs ("Valium without the sedation") that will represent the first major advance in the treatment of anxiety disorders for over 50 years. Anxiety disorders are the most common cause of patients visiting their GP and of these, generalized anxiety disorder (GAD) is the most prevalent. It affects around 5% of the population at some time in their life and is characterized by persistent, pervasive and excessive worrying. Consequently, it is a debilitating disorder that has an impact on society that is equivalent to depression and costs the UK in the region of £10 billion a year. Current treatments for GAD are unsatisfactory for various reasons and there have been no major innovations since benzodiazepines were introduced in the early 1960s. Benzodiazepines are a class of so-called minor tranquilizer drugs the most famous of which is diazepam (Valium, aka "Mother's Little Helper"). Benzodiazepines are effective at reducing anxiety (i.e., they are anxiolytics) but sedation is a major side-effect. Until recently, all attempts to identify next-generation drugs that "dial-out" these side-effects, particularly the sedation, have been unsuccessful. However, following recent advances in our knowledge of how benzodiazepines work, we are now in a position to understand what is required to develop a non-sedating anxiolytic and, more importantly, how we can identify such drugs. It is these breakthroughs in our knowledge that this proposal aims to exploit. Benzodiazepines act by altering the effects of a chemical in the brain (neurotransmitter) called gamma-aminobutyric acid (GABA). This neurotransmitter bind to four similar proteins in the brain called alpha1, alpha2, alpha3 and alpha5 GABAA receptors (GABAAR). Recent data suggests that the alpha1 subtype is responsible for sedation and consequently, it is hypothesised that by specifically affecting the alpha2 and alpha3 (the "anxiolytic") GABAAR subtypes while avoiding the alpha1 (the "sedation") subtype, it should be possible to identify an anxiolytic compound which is non-sedating. This hypothesis turns out to be correct with many experiments in animals showing that a GABAAR alpha2/alpha3 drug is indeed a non-sedating anxiolytic and early studies in man also support this hypothesis. Previous GABAAR alpha2/alpha3 drugs that were tested in man are no longer being developed due to a number of reasons unrelated to their mechanism of action and we therefore wish to continue with this area of research and develop novel GABAAR alpha2/alpha3 drugs that have the potential to revolutionize the treatment of anxiety disorders in general and GAD in particular.